NK1 receptor antagonist
Encyclopedia
Neurokinin 1 antagonists are a novel class of medications that possesses unique antidepressant
, anxiolytic
, and antiemetic
properties. The discovery of neurokinin 1 (NK1
) receptor antagonists was a turning point in the prevention of nausea and vomiting associated with cancer chemotherapy
.
An example of a drug in this class is aprepitant
. Chemotherapy-induced emesis appears to consist of acute and delayed phases. So far, the acute phase emesis responds to 5-HT3 antagonists
while the delayed phase remains difficult to control. The discovery and development of NK1 receptor antagonists have elicited antiemetic effect in both acute and especially in delayed phases of emesis.
The first registered clinical use of NK1 receptor antagonists was the treatment of emesis, associated with cancer chemotherapy
.
in horse brain and intestine. The substance showed strong vasodilatory
effects and contractile activity on the rabbit gut. A great effort was put in to purifying this substance from diverse mammalian tissue, but 30 years of research were without success. Nonmammalian peptide
s that elicited the same vasodilatory and contractile effects as SP were discovered by Erspamer in the early 1960s. These peptide
s had a common C-terminal sequence, and were grouped together as tachykinins. In 1971, Chang managed to purify SP from horse intestine and identify its amino acid
sequence; SP was then classified as a mammalian tachykinin. In the 1970s, it became clear that SP was a neuropeptide
that was common in the central and peripheral nervous system
. In the mid 1980s, the additional mammalian tachykinin neurokinin A (NKA) and neurokinin B (NKB) were discovered. This led to further research, resulting in the isolation of the genes that encoded the mammalian tachykinins and eventually the discovery of three different tachykinin receptors. In 1984, it was decided that the tachykinin receptors should be called tachykinin NK1 receptor, tachykinin NK2 receptor and tachykinin NK3 receptor.
Biological research that identified the many functions of tachykinins sparked interest in neurokinin receptor antagonist
s development. In the 1980s, several peptide
antagonists derived from SP were the first NK1 receptor antagonists. However, these compounds, like most peptide compounds, had problems with selectivity
, potency
, solubility
and bioavailability
. For this reason, pharmaceutical companies concentrated on developing non-peptide NK1 receptor antagonists, and in 1991, three different companies revealed their first results. Since then, non-peptide NK1 receptor antagonists have been researched extensively and many structures and patent
s have appeared. In 2003, the first NK1 receptor antagonist, aprepitant (Emend), received marketing approval from the U.S. Food and Drug Administration (FDA).
s that share the same hydrophobic
C-terminal region with the amino acid
sequence Phe
-X-Gly
-Leu
-Met
-NH2, where X represents a hydrophobic residue that is either an aromatic or a beta-branched aliphatic. The N-terminal region varies between different tachykinins. The term tachykinin originates in the rapid onset of action caused by the peptides in smooth muscles. SP is the most researched and potent member of the tachykinin family. It is an undecapeptide with the amino acid
sequence Arg
-Pro
-Lys
-Pro
-Gln
-Gln
-Phe
-Phe
-Gly
-Leu
-Met
-NH2. SP binds to all three of the tachykinin receptors, but it binds most strongly to the NK1 receptor.
Tachykinin NK1 receptor, often referred to as NK1 receptor, is a member of family 1 (rhodopsin
-like) of G protein-coupled receptors. NK1 receptor consists of 407 amino acid residues, and it has a molecular weight of 58.000. NK1 receptor, as well as the other tachykinin receptors, is made of seven hydrophobic transmembrane (TM) domains with three extracellular
and three intracellular
loops, an amino-terminus and a cytoplasmic carboxy-terminus. The loops have functional sites, including two cysteines amino acids for a disulfide bridge, Asp
-Arg
-Tyr
, which is responsible for association with arrestin
and, Lys
/Arg
-Lys
/Arg
-X-X-Lys
/Arg
, which interacts with G-proteins.
In 1991, three different groups researched different NK1 receptor antagonists by screening
of chemical collections. Eastman Kodak and Sterling Winthrop discovered steroid
series of tachykinin NK1 receptor antagonists that yielded some compounds but lacked sufficient affinity for the NK1 receptor, despite structure-activity relationship
(SAR) studies that were performed. This series proved to have significant toxicity. Even though many derivatives of the steroid
compounds have been synthesized, biological activity has not been improved.
Rhone-Poulnec discovered the compound RP-67580, which has high affinity for the NK1 receptor in rats and mice, but not in humans. SAR studies that were performed in order to improve the selectivity
for the human NK1 receptor resulted in the development of a compound called RPR-100893. This compound showed good activity in vivo and in models of pain and was developed up to phase II for the treatment of migraines but then terminated, as was the case with other NK1 receptor antagonists that were tested for the same indication.
The third company, Pfizer
, discovered a benzylamino
quinuclidine
structure, which was called CP-96345 (figure 1). CP-96345 has a rather simple structure, composed of a rigid quinuclidine scaffold containing a basic nitrogen atom, a benzhydril moiety
and an o-methoxy-benzylamine group. This compound showed high affinity for the NK1 receptor, but it also interacted with Ca2+ binding sites. Strongly basic quinuclidine nitrogen on the compound was considered to be responsible for this Ca2+ binding, which caused a number of systemic effects, unrelated to the blocking of the NK1 receptor. For that reason and also to simplify the structure, alkylation
at this site was performed to produce analogs.
The compound CP-99994 was synthesized by replacing the quinuclidine
ring with a piperidine
ring and benzhydryl moiety
by a benzyl
group (figure 2). CP-99994 had a high affinity for the human NK1 receptor and it started a great amount of structure–activity studies, each intending to identify the structural requirements for high-affinity interaction with the NK1 receptor, and to make the molecule even simpler and improve its chemico-physical and pharmacological properties. CP-99994 eased dental pain in humans and entered phase II clinical trials; these were discontinued because of poor bioavailability. Pfizer researched several other related NK1 receptor antagonists. CJ-11974, also called ezlopitant, was a close analog of CP-96345 that had an isopropyl group on the methoxybenzyl ring. It was developed up to phase II clinical trials for chemotherapy-induced emesis before development was discontinued. CP-122721 was a CP-99994 analog that had a trifluoromethoxy group in the o-methoxybenzyl ring. It entered phase II trials for the treatment of depression, emesis and inflammatory diseases, but no further development has been reported.
started performing SAR studies of NK1 receptor antagonists, based on both CP-96345 and CP-99994. L-733,060
is one of the compounds that were developed from CP-99994. It has a 3,5-bistrifluoromethyl benzylether piperidine
in place of 2-methoxy benzylamine
moiety
of CP-99994 compound. To improve oral bioavailability, the piperidine nitrogen was functionalized in order to reduce its basic nature. The group that gave the best effects on basicity was 3-oxo-1,2,4-triazol-5-yl moiety and it gave compounds such as L-741671 and L-742694.
A morpholine
nucleus that was introduced in L-742694 was found to enhance NK1 binding affinity. This nucleus was preserved in further modifications. In order to prevent possible metabolic deactivation, several refinements such as methylation
on the C alfa of the benzyl ring
and fluorination on the phenyl ring were introduced. These changes produced the compound MK-869, which showed high affinity for the NK1 receptor and high oral activity (figure 3). MK-869 is also called aprepitant
, and was studied in pain, migraines, emesis and psychiatric disorders. These studies led to the FDA-approved drug Emend
for chemo therapy-induced nausea and vomiting, and is available for oral use. A water-soluble phosphoryl prodrug for intravenous use, called fosaprepitant
, is also available and is marketed as Ivemend. Aprepitant
was also believed to be effective in the treatment of depression. It entered phase III trials before the development for this indication was discontinued.
Many different compounds have been described by various pharmaceutical companies besides the compounds that led to the discovery of aprepitant. GR-205171 (figure 4) was developed by Glaxo
and was based on CP-99994. GR-205171 had a tetrazole
ring in position 4 of the benzyl
ring of CP-99994 that was intended to increase oral bioavailability and improve pharmacokinetic properties. It was developed up to phase II clinical trials for the treatment of postoperative nausea and vomiting, migraine and motion sickness. It showed good results in emesis, but development was discontinued.
LY-303870, or lanepitant (figure 5), is an N-acetylated reduced amide of L-tryptophan that was discovered by Eli Lilly
. It underwent phase IIa clinical trials for the treatment of osteoarthritis pain but showed no significant effects. Eli Lilly made some SAR work on its structure and developed some compounds that did not enter clinical trials.
By a general hypothesis on peptideric G protein-coupled receptors binding site, Takeda discovered a series of N-benzylcarboxyamides in 1995. One of those compounds, TAK-637 (figure 6), underwent phase II clinical trials for urinary incontinence, depression and irritable bowel syndrome, but the development was discontinued. There are still other compounds that have been researched in the past and even reached clinical trials, and research continues despite the lack of success in clinical trials.
, and these binding domains can be found in various places. The main ligand binding site is in the hydrophobic core between the loops and the outer segments of transmembrane domains 3–7 (TM3–TM7).
Several residues, such as Gln
165 (TM4), His
197 (TM5), His265 (TM6) and Tyr
287 (TM7) are involved in the binding of many non-peptide antagonists
of the NK1 receptors.
It has been stated that Ala
-replacement of His197 decreases the binding affinity of CP-96345 for the NK1 receptor. His197 interacts with the benzhydryl
moiety of CP-96345.
Experiments have showed that replacing Val
116 (TM3) and Ile
290 (TM7) decreases the binding affinity of CP-96345. Evidence indicates that these residues probably do not interact with antagonists, but would rather indirectly influence the overall conformation of the antagonist binding site.
The residue Gln
165 (TM4) has also proven to be meaningful for the binding of several non-peptide antagonists, possibly through the formation of a hydrogen bond
.
Phe
268 and Tyr
287 have been proposed as possible contact points for both agonist and antagonist binding domains.
The significance of His265 has been confirmed in the binding of antagonists to NK1 receptor. His265 interacts favorably with the 3,5-bis-trifluoromethylphenyl group (TFMP group) of an analog CP-96345. Nonetheless, it has been demonstrated that Ala-replacement of His265 does not affect the binding affinity of CP-96345.
Some other residues that are thought to be involved in the binding of non-peptide antagonists to NK1 receptor are Ser
169, Glu
193, Lys
194, Phe
264, Phe
267, Pro
271 and Tyr
272.
Each structural class of non-peptide NK1 receptor antagonists appears to interact with a specific set of residues within the common binding pocket.
group; and third, the specific site interactivity with the (2-methoxybenzyl) amino side chain.
Studies have shown that compounds with piperidine
ring have selectivity for NK1 receptor over NK2, NK3, opioid
and 5-HT
receptors. By adding an N-heteroaryl-2-phenyl-3-(benzyloxy) group to the piperidine
, a selective NK1 receptor antagonist is produced. Studies have also shown that the dihedral angle between groups on C-2 and C-3 in CP-99994 is critical for activity of the NK1 receptor antagonists. The bridgehead basic nitrogen is thought to interact with the NK1 receptor by mediating its recognition through ion pair site. It has been found that the basic nitrogen atoms in pyrido[3,4-b]pyridine do have an anchoring function in the phospholipid component of the cell membrane.
In the development of MK-869, it was discovered that 3,5-disubstitution of the benzyl ring in the ether series gave greater potency than the 2-methoxy substitution
in earlier benzylamine
structures. It also was revealed that the TFMP group appeared to be especially important, and it is believed that it enhances activity in vivo and improves metabolism. Other groups, like the ortho-methoxyphenyl group, can be important in specific cases, but are thought to play a greater role in ligand preorganization through intramolecular hydrogen bonding, rather than through direct interaction with binding site residue.
The presence of an intramolecular face-to-face π–π interaction between two aromatic rings
is a common feature of high affinity NK1 receptor antagonists. This feature is thought to be important in stabilizing the bioactive conformation. This interaction can be increased with a conformationally-restricted system, such as an eight-membered ring introduced into the naphthyridine ring.
Chemotherapy-induced emesis is a major problem in cancer treatment. A new compound, T-2328 (figure 7), a non-peptide antagonist
of the tachykinin NK1 family, is studied for that purpose. T-2328 is administered intravenously, and treats both acute and delayed emesis. It is proposed to exert its anti-emetic
effect through acting on brain NK1 receptors. T-2328 is very potent; the inhibition constant
is of subnanomolar range and is 16 times lower than that of aprepitant. The inhibition is highly selective for NK1 receptors.
The NK2
and NK3
receptors are also targets for novel classes of medications, and also show prominent antidepressive and anxiolytic effects. Studies showed that the inhibition constant
(Ki) for NK2 receptors was >10000-fold higher and for NK3 receptors >1000-fold higher than that for NK1 receptors. The affinity was also much lower for NK2 and NK3 receptors.
Since tachykinins were discovered, they have been shown to possess biological activity in number of pathological
and physiological
systems. Nevertheless, the therapeutic potential of the tachykinin antagonists has not been fully understood.
variants, which at the same time are translated into four NK1R isoforms that have different affinities to substance P (known to play a main role in lowering stress response when working on these receptors). The purpose of the study was to investigate whether these genetic variants of NK1R are related to alcohol dependence. The study used 337 Caucasian subjects as the control and 271 Caucasian subjects that were diagnosed with alcohol dependence. White blood cells from each subject were obtained and 11 single nucleotide polymorphisms (SNPs) across the NK1R gene were genotyped. After examination, as both individual SNPs and at the haplotype level, it was discovered that the rs6715729 SNP showed a significant difference of the genotypic and allelic frequency between the two groups. At the haplotype level, they found two risk haplotypes for alcohol dependence that were formed from a combination of 3 SNPs, rs6715729, rs735668 and rs6741029, that also showed a significant difference between the two groups. Thus these polymorphisms of the NK1R gene are indeed associated with the development of alcohol dependence.
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
, anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
, and antiemetic
Antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
properties. The discovery of neurokinin 1 (NK1
Tachykinin receptor 1
The tachykinin receptor 1 also known as neurokinin 1 receptor or substance P receptor is a G protein coupled receptor found in the central nervous system and peripheral nervous system. The endogenous ligand for this receptor is Substance P, although it has some affinity for other tachykinins...
) receptor antagonists was a turning point in the prevention of nausea and vomiting associated with cancer chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
.
An example of a drug in this class is aprepitant
Aprepitant
Aprepitant is an antiemetic chemical compound that belongs to a class of drugs called substance P antagonists . It mediates its effect by blocking the neurokinin 1 receptor.Aprepitant is manufactured by Merck & Co...
. Chemotherapy-induced emesis appears to consist of acute and delayed phases. So far, the acute phase emesis responds to 5-HT3 antagonists
5-HT3 antagonist
The 5-HT3 antagonists are a class of medications that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain....
while the delayed phase remains difficult to control. The discovery and development of NK1 receptor antagonists have elicited antiemetic effect in both acute and especially in delayed phases of emesis.
The first registered clinical use of NK1 receptor antagonists was the treatment of emesis, associated with cancer chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
.
History
In 1931, von Euler and Gaddum discovered substance P (SP)Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
in horse brain and intestine. The substance showed strong vasodilatory
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
effects and contractile activity on the rabbit gut. A great effort was put in to purifying this substance from diverse mammalian tissue, but 30 years of research were without success. Nonmammalian peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
s that elicited the same vasodilatory and contractile effects as SP were discovered by Erspamer in the early 1960s. These peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
s had a common C-terminal sequence, and were grouped together as tachykinins. In 1971, Chang managed to purify SP from horse intestine and identify its amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence; SP was then classified as a mammalian tachykinin. In the 1970s, it became clear that SP was a neuropeptide
Neuropeptide
Neuropeptides are small protein-like molecules used by neurons to communicate with each other. They are neuronal signaling molecules, influence the activity of the brain in specific ways and are thus involved in particular brain functions, like analgesia, reward, food intake, learning and...
that was common in the central and peripheral nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
. In the mid 1980s, the additional mammalian tachykinin neurokinin A (NKA) and neurokinin B (NKB) were discovered. This led to further research, resulting in the isolation of the genes that encoded the mammalian tachykinins and eventually the discovery of three different tachykinin receptors. In 1984, it was decided that the tachykinin receptors should be called tachykinin NK1 receptor, tachykinin NK2 receptor and tachykinin NK3 receptor.
Biological research that identified the many functions of tachykinins sparked interest in neurokinin receptor antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
s development. In the 1980s, several peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
antagonists derived from SP were the first NK1 receptor antagonists. However, these compounds, like most peptide compounds, had problems with selectivity
Functional Selectivity
Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways in one and the same receptor. This can be present when a receptor has several possible signal transduction pathways...
, potency
Potency (pharmacology)
In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations, while a drug of lower potency evokes a small response at low concentrations...
, solubility
Solubility
Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. The solubility of a substance fundamentally depends on the used solvent as well as on...
and bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
. For this reason, pharmaceutical companies concentrated on developing non-peptide NK1 receptor antagonists, and in 1991, three different companies revealed their first results. Since then, non-peptide NK1 receptor antagonists have been researched extensively and many structures and patent
Patent
A patent is a form of intellectual property. It consists of a set of exclusive rights granted by a sovereign state to an inventor or their assignee for a limited period of time in exchange for the public disclosure of an invention....
s have appeared. In 2003, the first NK1 receptor antagonist, aprepitant (Emend), received marketing approval from the U.S. Food and Drug Administration (FDA).
The neurokinin-1 receptor
Tachykinins are a family of neuropeptideNeuropeptide
Neuropeptides are small protein-like molecules used by neurons to communicate with each other. They are neuronal signaling molecules, influence the activity of the brain in specific ways and are thus involved in particular brain functions, like analgesia, reward, food intake, learning and...
s that share the same hydrophobic
Hydrophobe
In chemistry, hydrophobicity is the physical property of a molecule that is repelled from a mass of water....
C-terminal region with the amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence Phe
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
-X-Gly
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
-Leu
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
-Met
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
-NH2, where X represents a hydrophobic residue that is either an aromatic or a beta-branched aliphatic. The N-terminal region varies between different tachykinins. The term tachykinin originates in the rapid onset of action caused by the peptides in smooth muscles. SP is the most researched and potent member of the tachykinin family. It is an undecapeptide with the amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence Arg
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
-Pro
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
-Lys
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
-Pro
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
-Gln
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
-Gln
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
-Phe
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
-Phe
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
-Gly
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
-Leu
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
-Met
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
-NH2. SP binds to all three of the tachykinin receptors, but it binds most strongly to the NK1 receptor.
Tachykinin NK1 receptor, often referred to as NK1 receptor, is a member of family 1 (rhodopsin
Rhodopsin
Rhodopsin, also known as visual purple, is a biological pigment of the retina that is responsible for both the formation of the photoreceptor cells and the first events in the perception of light. Rhodopsins belong to the G-protein coupled receptor family and are extremely sensitive to light,...
-like) of G protein-coupled receptors. NK1 receptor consists of 407 amino acid residues, and it has a molecular weight of 58.000. NK1 receptor, as well as the other tachykinin receptors, is made of seven hydrophobic transmembrane (TM) domains with three extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
and three intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
loops, an amino-terminus and a cytoplasmic carboxy-terminus. The loops have functional sites, including two cysteines amino acids for a disulfide bridge, Asp
Aspartic acid
Aspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...
-Arg
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
-Tyr
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
, which is responsible for association with arrestin
Arrestin
Arrestins are a small family of proteins important for regulating signal transduction.-Function:Arrestins were first discovered as a part of a conserved two-step mechanism for regulating the activity of G protein-coupled receptors in the visual rhodopsin system by Hermann Kühn and co-workers and...
and, Lys
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
/Arg
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
-Lys
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
/Arg
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
-X-X-Lys
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
/Arg
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
, which interacts with G-proteins.
Drug discovery and development
Screening (medicine)
Screening, in medicine, is a strategy used in a population to detect a disease in individuals without signs or symptoms of that disease. Unlike what generally happens in medicine, screening tests are performed on persons without any clinical sign of disease....
of chemical collections. Eastman Kodak and Sterling Winthrop discovered steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
series of tachykinin NK1 receptor antagonists that yielded some compounds but lacked sufficient affinity for the NK1 receptor, despite structure-activity relationship
Structure-activity relationship
The structure–activity relationship is the relationship between the chemical or 3D structure of a molecule and its biological activity. The analysis of SAR enables the determination of the chemical groups responsible for evoking a target biological effect in the organism...
(SAR) studies that were performed. This series proved to have significant toxicity. Even though many derivatives of the steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
compounds have been synthesized, biological activity has not been improved.
Rhone-Poulnec discovered the compound RP-67580, which has high affinity for the NK1 receptor in rats and mice, but not in humans. SAR studies that were performed in order to improve the selectivity
Functional Selectivity
Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways in one and the same receptor. This can be present when a receptor has several possible signal transduction pathways...
for the human NK1 receptor resulted in the development of a compound called RPR-100893. This compound showed good activity in vivo and in models of pain and was developed up to phase II for the treatment of migraines but then terminated, as was the case with other NK1 receptor antagonists that were tested for the same indication.
The third company, Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
, discovered a benzylamino
Benzylamine
Benzylamine is the chemical compound with the formula C6H5CH2NH2. It consists of a benzyl group, C6H5CH2, attached to an amine functional group...
quinuclidine
Quinuclidine
Quinuclidine is an organic compound and a bicyclic amine and used as a catalyst and a chemical building block. It is a strong base with pKa of the conjugate acid of 11.0. This is due to greater availability of the nitrogen lone pair...
structure, which was called CP-96345 (figure 1). CP-96345 has a rather simple structure, composed of a rigid quinuclidine scaffold containing a basic nitrogen atom, a benzhydril moiety
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
and an o-methoxy-benzylamine group. This compound showed high affinity for the NK1 receptor, but it also interacted with Ca2+ binding sites. Strongly basic quinuclidine nitrogen on the compound was considered to be responsible for this Ca2+ binding, which caused a number of systemic effects, unrelated to the blocking of the NK1 receptor. For that reason and also to simplify the structure, alkylation
Alkylation
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion or a carbene . Alkylating agents are widely used in chemistry because the alkyl group is probably the most common group encountered in...
at this site was performed to produce analogs.
The compound CP-99994 was synthesized by replacing the quinuclidine
Quinuclidine
Quinuclidine is an organic compound and a bicyclic amine and used as a catalyst and a chemical building block. It is a strong base with pKa of the conjugate acid of 11.0. This is due to greater availability of the nitrogen lone pair...
ring with a piperidine
Piperidine
Piperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...
ring and benzhydryl moiety
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
by a benzyl
Benzyl
In organic chemistry, benzyl is the term used to describe the substituent or molecular fragment possessing the structure C6H5CH2-. Benzyl features a benzene ring attached to a CH2 group.-Nomenclature:...
group (figure 2). CP-99994 had a high affinity for the human NK1 receptor and it started a great amount of structure–activity studies, each intending to identify the structural requirements for high-affinity interaction with the NK1 receptor, and to make the molecule even simpler and improve its chemico-physical and pharmacological properties. CP-99994 eased dental pain in humans and entered phase II clinical trials; these were discontinued because of poor bioavailability. Pfizer researched several other related NK1 receptor antagonists. CJ-11974, also called ezlopitant, was a close analog of CP-96345 that had an isopropyl group on the methoxybenzyl ring. It was developed up to phase II clinical trials for chemotherapy-induced emesis before development was discontinued. CP-122721 was a CP-99994 analog that had a trifluoromethoxy group in the o-methoxybenzyl ring. It entered phase II trials for the treatment of depression, emesis and inflammatory diseases, but no further development has been reported.
Development of the first drug
In 1993, MerckMerck & Co.
Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...
started performing SAR studies of NK1 receptor antagonists, based on both CP-96345 and CP-99994. L-733,060
L-733,060
L-733,060 is a drug developed by Merck, Sharpe & Dohme which acts as an orally active, non-peptide, selective antagonist for the NK1 receptor, binding with a Ki of 0.08nM...
is one of the compounds that were developed from CP-99994. It has a 3,5-bistrifluoromethyl benzylether piperidine
Piperidine
Piperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...
in place of 2-methoxy benzylamine
Benzylamine
Benzylamine is the chemical compound with the formula C6H5CH2NH2. It consists of a benzyl group, C6H5CH2, attached to an amine functional group...
moiety
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
of CP-99994 compound. To improve oral bioavailability, the piperidine nitrogen was functionalized in order to reduce its basic nature. The group that gave the best effects on basicity was 3-oxo-1,2,4-triazol-5-yl moiety and it gave compounds such as L-741671 and L-742694.
A morpholine
Morpholine
Morpholine is an organic chemical compound having the chemical formula O2NH. This heterocycle, pictured at right, features both amine and ether functional groups. Because of the amine, morpholine is a base; its conjugate acid is called morpholinium...
nucleus that was introduced in L-742694 was found to enhance NK1 binding affinity. This nucleus was preserved in further modifications. In order to prevent possible metabolic deactivation, several refinements such as methylation
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
on the C alfa of the benzyl ring
Benzyl
In organic chemistry, benzyl is the term used to describe the substituent or molecular fragment possessing the structure C6H5CH2-. Benzyl features a benzene ring attached to a CH2 group.-Nomenclature:...
and fluorination on the phenyl ring were introduced. These changes produced the compound MK-869, which showed high affinity for the NK1 receptor and high oral activity (figure 3). MK-869 is also called aprepitant
Aprepitant
Aprepitant is an antiemetic chemical compound that belongs to a class of drugs called substance P antagonists . It mediates its effect by blocking the neurokinin 1 receptor.Aprepitant is manufactured by Merck & Co...
, and was studied in pain, migraines, emesis and psychiatric disorders. These studies led to the FDA-approved drug Emend
Aprepitant
Aprepitant is an antiemetic chemical compound that belongs to a class of drugs called substance P antagonists . It mediates its effect by blocking the neurokinin 1 receptor.Aprepitant is manufactured by Merck & Co...
for chemo therapy-induced nausea and vomiting, and is available for oral use. A water-soluble phosphoryl prodrug for intravenous use, called fosaprepitant
Fosaprepitant
Fosaprepitant is an antiemetic drug, administered intravenously. It is a prodrug of aprepitant....
, is also available and is marketed as Ivemend. Aprepitant
Aprepitant
Aprepitant is an antiemetic chemical compound that belongs to a class of drugs called substance P antagonists . It mediates its effect by blocking the neurokinin 1 receptor.Aprepitant is manufactured by Merck & Co...
was also believed to be effective in the treatment of depression. It entered phase III trials before the development for this indication was discontinued.
Other compounds
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
and was based on CP-99994. GR-205171 had a tetrazole
Tetrazole
Tetrazoles are a class of synthetic organic heterocyclic compound, consisting of a 5-member ring of four nitrogen and one carbon atom . The simplest is tetrazole itself, CN4H2. They are unknown in nature...
ring in position 4 of the benzyl
Benzyl
In organic chemistry, benzyl is the term used to describe the substituent or molecular fragment possessing the structure C6H5CH2-. Benzyl features a benzene ring attached to a CH2 group.-Nomenclature:...
ring of CP-99994 that was intended to increase oral bioavailability and improve pharmacokinetic properties. It was developed up to phase II clinical trials for the treatment of postoperative nausea and vomiting, migraine and motion sickness. It showed good results in emesis, but development was discontinued.
LY-303870, or lanepitant (figure 5), is an N-acetylated reduced amide of L-tryptophan that was discovered by Eli Lilly
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
. It underwent phase IIa clinical trials for the treatment of osteoarthritis pain but showed no significant effects. Eli Lilly made some SAR work on its structure and developed some compounds that did not enter clinical trials.
By a general hypothesis on peptideric G protein-coupled receptors binding site, Takeda discovered a series of N-benzylcarboxyamides in 1995. One of those compounds, TAK-637 (figure 6), underwent phase II clinical trials for urinary incontinence, depression and irritable bowel syndrome, but the development was discontinued. There are still other compounds that have been researched in the past and even reached clinical trials, and research continues despite the lack of success in clinical trials.
Binding
There is more than one ligand binding domain on the NK1 receptor for the non-peptide antagonistsReceptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
, and these binding domains can be found in various places. The main ligand binding site is in the hydrophobic core between the loops and the outer segments of transmembrane domains 3–7 (TM3–TM7).
Several residues, such as Gln
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
165 (TM4), His
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
197 (TM5), His265 (TM6) and Tyr
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
287 (TM7) are involved in the binding of many non-peptide antagonists
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
of the NK1 receptors.
It has been stated that Ala
Alanine
Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
-replacement of His197 decreases the binding affinity of CP-96345 for the NK1 receptor. His197 interacts with the benzhydryl
Benzhydryl compounds
Benzhydryl compounds are compounds that are "diphenylmethane" containing, i.e. two benzene rings adjoined by a single carbon. This simple definition does not include heteroaromatic ring moieties, which would grossify the situation even further...
moiety of CP-96345.
Experiments have showed that replacing Val
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
116 (TM3) and Ile
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
290 (TM7) decreases the binding affinity of CP-96345. Evidence indicates that these residues probably do not interact with antagonists, but would rather indirectly influence the overall conformation of the antagonist binding site.
The residue Gln
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
165 (TM4) has also proven to be meaningful for the binding of several non-peptide antagonists, possibly through the formation of a hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
.
Phe
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
268 and Tyr
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
287 have been proposed as possible contact points for both agonist and antagonist binding domains.
The significance of His265 has been confirmed in the binding of antagonists to NK1 receptor. His265 interacts favorably with the 3,5-bis-trifluoromethylphenyl group (TFMP group) of an analog CP-96345. Nonetheless, it has been demonstrated that Ala-replacement of His265 does not affect the binding affinity of CP-96345.
Some other residues that are thought to be involved in the binding of non-peptide antagonists to NK1 receptor are Ser
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
169, Glu
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
193, Lys
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
194, Phe
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
264, Phe
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
267, Pro
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
271 and Tyr
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
272.
Each structural class of non-peptide NK1 receptor antagonists appears to interact with a specific set of residues within the common binding pocket.
Structure-activity relationship (SAR) and pharmacophore
There are at least three essential elements which are important for the interactivity of a ligand with the NK1 receptor. First, the ion-pair site interactivity with the bridgehead nitrogen; second, the accessory binding site interactivity with the benzhydrylBenzhydryl compounds
Benzhydryl compounds are compounds that are "diphenylmethane" containing, i.e. two benzene rings adjoined by a single carbon. This simple definition does not include heteroaromatic ring moieties, which would grossify the situation even further...
group; and third, the specific site interactivity with the (2-methoxybenzyl) amino side chain.
Studies have shown that compounds with piperidine
Piperidine
Piperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...
ring have selectivity for NK1 receptor over NK2, NK3, opioid
Opioid receptor
Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors...
and 5-HT
5-HT receptor
The serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission...
receptors. By adding an N-heteroaryl-2-phenyl-3-(benzyloxy) group to the piperidine
Piperidine
Piperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...
, a selective NK1 receptor antagonist is produced. Studies have also shown that the dihedral angle between groups on C-2 and C-3 in CP-99994 is critical for activity of the NK1 receptor antagonists. The bridgehead basic nitrogen is thought to interact with the NK1 receptor by mediating its recognition through ion pair site. It has been found that the basic nitrogen atoms in pyrido[3,4-b]pyridine do have an anchoring function in the phospholipid component of the cell membrane.
In the development of MK-869, it was discovered that 3,5-disubstitution of the benzyl ring in the ether series gave greater potency than the 2-methoxy substitution
Substitution reaction
In a substitution reaction, a functional group in a particular chemical compound is replaced by another group. In organic chemistry, the electrophilic and nucleophilic substitution reactions are of prime importance...
in earlier benzylamine
Benzylamine
Benzylamine is the chemical compound with the formula C6H5CH2NH2. It consists of a benzyl group, C6H5CH2, attached to an amine functional group...
structures. It also was revealed that the TFMP group appeared to be especially important, and it is believed that it enhances activity in vivo and improves metabolism. Other groups, like the ortho-methoxyphenyl group, can be important in specific cases, but are thought to play a greater role in ligand preorganization through intramolecular hydrogen bonding, rather than through direct interaction with binding site residue.
The presence of an intramolecular face-to-face π–π interaction between two aromatic rings
Aromaticity
In organic chemistry, Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. The earliest use of the term was in an article by August...
is a common feature of high affinity NK1 receptor antagonists. This feature is thought to be important in stabilizing the bioactive conformation. This interaction can be increased with a conformationally-restricted system, such as an eight-membered ring introduced into the naphthyridine ring.
Future development
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
of the tachykinin NK1 family, is studied for that purpose. T-2328 is administered intravenously, and treats both acute and delayed emesis. It is proposed to exert its anti-emetic
Antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
effect through acting on brain NK1 receptors. T-2328 is very potent; the inhibition constant
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
is of subnanomolar range and is 16 times lower than that of aprepitant. The inhibition is highly selective for NK1 receptors.
The NK2
Tachykinin receptor 2
Substance-K receptor is a protein that in humans is encoded by the TACR2 gene.-Selective Ligands:Several selective ligands for NK2 are now available, and although most of the compounds developed so far are peptides, one small-molecule antagonist Saredutant is currently in clinical trials as an...
and NK3
Tachykinin receptor 3
Tachykinin receptor 3, also known as TACR3, is a protein which in humans is encoded by the TACR3 gene.- Function :This gene belongs to a family of genes that function as receptors for tachykinins. Receptor affinities are specified by variations in the 5'-end of the sequence...
receptors are also targets for novel classes of medications, and also show prominent antidepressive and anxiolytic effects. Studies showed that the inhibition constant
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
(Ki) for NK2 receptors was >10000-fold higher and for NK3 receptors >1000-fold higher than that for NK1 receptors. The affinity was also much lower for NK2 and NK3 receptors.
Since tachykinins were discovered, they have been shown to possess biological activity in number of pathological
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
and physiological
Physiology
Physiology is the science of the function of living systems. This includes how organisms, organ systems, organs, cells, and bio-molecules carry out the chemical or physical functions that exist in a living system. The highest honor awarded in physiology is the Nobel Prize in Physiology or...
systems. Nevertheless, the therapeutic potential of the tachykinin antagonists has not been fully understood.
New discoveries about the NK1 receptor
In 2009, it was found that the NK1R gene is transcribed in four mRNAMessenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
variants, which at the same time are translated into four NK1R isoforms that have different affinities to substance P (known to play a main role in lowering stress response when working on these receptors). The purpose of the study was to investigate whether these genetic variants of NK1R are related to alcohol dependence. The study used 337 Caucasian subjects as the control and 271 Caucasian subjects that were diagnosed with alcohol dependence. White blood cells from each subject were obtained and 11 single nucleotide polymorphisms (SNPs) across the NK1R gene were genotyped. After examination, as both individual SNPs and at the haplotype level, it was discovered that the rs6715729 SNP showed a significant difference of the genotypic and allelic frequency between the two groups. At the haplotype level, they found two risk haplotypes for alcohol dependence that were formed from a combination of 3 SNPs, rs6715729, rs735668 and rs6741029, that also showed a significant difference between the two groups. Thus these polymorphisms of the NK1R gene are indeed associated with the development of alcohol dependence.
See also
- CasopitantCasopitantCasopitant is an neurokinin 1 receptor antagonist undergoing research for the treatment of chemotherapy-induced nausea and vomiting . It is currently under development by GlaxoSmithKline ....
- MaropitantMaropitantMaropitant , used as maropitant citrate , is a neurokinin receptor antagonist, which was developed by Pfizer Animal Health specifically for the treatment of motion sickness and vomiting in dogs. It has not been approved by the FDA for use in any animal except dogs...
- Tachykinin receptorTachykinin receptorThere are three known mammalian tachykinin receptors termed NK1, NK2 and NK3. All are members of the 7 transmembrane G-protein coupled receptor family and induce the activation of phospholipase C, producing inositol triphosphate ....
- G protein-coupled receptors