Discovery and development of melatonin receptor agonists
Encyclopedia
Melatonin receptor agonists are analogues of melatonin
that bind to and activate the melatonin receptor
. Agonist
s of the melatonin receptor have a number of therapeutic applications including treatment of sleep disorders and depression. The discovery and development of melatonin receptor agonists was motivated by the need for more potent analogues than melatonin
, with better pharmacokinetics
and longer half-life
. Melatonin receptor agonists are analogues of melatonin and were developed with the melatonin structure as a model.
The melatonin receptors are G protein-coupled receptors and are expressed in various tissues of the body. There are two subtypes of the receptor in humans, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). Melatonin and melatonin receptor agonist
s, on market or in clinical trials, all bind to and activate both receptor types. The binding of the agonists to the receptors has been investigated for over two decades or since 1986. It is somewhat known, but still not fully understood. When melatonin receptor agonists bind to and activate their receptors it causes numerous physiological processes.
and his colleagues isolated the substance N-acetyl-5-methoxytryptamine and named it melatonin. High-affinity melatonin binding sites were pharmacologically characterized in the bovine brain in 1979. The first melatonergic receptor was cloned from melanophores of Xenopus laevis in the 1990s. In 1994 the melatonin receptors were characterized and cloned in the human being. There has been a constant growth in the field of melatonin and melatonin analogues since the 1980s. In 2005 ramelteon
(Rozerem®) was the first melatonin agonist to be approved in the United States (US), indicated for insomnia
treatment in adults which is characterized as difficulty with falling asleep. Melatonin in the form of the timed release Circadin® was approved in 2007 in Europe (EU) for use as a short-term treatment, in patients 55 years or older, for primary insomnia (poor quality of sleep). Products containing melatonin are available as a dietary supplement in the United States and Canada. In 2009 agomelatine (Valdoxan®, Melitor®, Thymanax®) was also approved in Europe and is indicated for the treatment of major depressive disorder in adults. Tasimelteon
completed the phase III clinical trial in the United States for primary insomnia in 2010. The Food and Drug Administration
(FDA) granted tasimelteon orphan drug
designation status for blind individuals without light perception with non-24-hour sleep-wake disorder
in January the same year. TIK-301 (PD-6735, LY-156,735
) has been in phase II clinical trial in the United States since 2002. The FDA granted TIK-301 orphan drug designation in May 2004, to use as a treatment for circadian rhythm sleep disorder
in blind individuals without light perception and individuals with tardive dyskinesia
.
and MT2
. They are G protein-coupled receptors and are expressed in various tissues of the body, together or singly. MT1 receptors are expressed in many regions of the central nervous system
(CNS): suprachiasmatic nucleus
of the hypothalamus (SNC), hippocampus
, substantia nigra
, cerebellum
, central dopaminergic pathways
, ventral tegmental area and nucleus accumbens
. MT1 is also expressed in the retina
, ovary
, testis, mammary gland
, coronary circulation
and aorta
, gallbladder
, liver, kidney, skin and the immune system
. MT2 receptors are expressed mainly in the CNS, also in the lung, cardiac, coronary and aortic tissue, myometrium
and granulosa cells, immune cells, duodenum
and adipocytes.
(cAMP), and then progressing to less protein kinase A (PKA) activity, which in turn hinders the phosphorilation of cAMP responsive element-binding protein (CREB binding protein
) into P-CREB. MT1 receptors also activate phospholipase C
(PLC), affect ion channels and regulate ion flux inside the cell. The binding of melatonin to MT2 receptors inhibits adenylyl cyclase which decreases the formation of cAMP. As well it hinders guanylyl cyclase and therefore the forming of cyclic guanosine monophosphate
(cGMP). Binding to MT2 receptors probably affects PLC which increases protein kinase C
(PKC) activity. Activation of the receptor can lead to ion flux inside the cell.
When melatonin receptor agonists activate their receptors it causes numerous physiological processes. MT1 and MT2 receptors may be a target for the treatment of circadian and non circadian sleep disorders because of their differences in pharmacology and function within the SCN. SCN is responsible for maintaining the 24 hour cycle which regulates many different body functions ranging from sleep to immune functions. Melatonin receptors have been identified in the cardiovascular system. Number of animal studies point to a dual role of melatonin in the vasculature. Activation of MT1 receptors mediates vasoconstriction and the activation of MT2 receptors mediates vasodilation. Melatonin is involved in regulating immune responses in both human and animals through activation of both MT1 and MT2 receptors. MT1 and MT2 receptors are widespread in the eye and are involved in regulating aqueous humor secretion, which is important for glaucoma
, and in phototransduction. This is not a complete list since many of the possible processes need further confirmation.
ring which is present in agomelatine (figure 4). Other ring systems have also showed melatonin agonist activity. Amongst them are indane
which is present in ramelteon (figure 4) and the ring system of tasimelteon (figure 4).
ring with methoxy
group in position 5 (5-methoxy group) and acylaminoethyl side-chain in position 3. The two side-chains are important for binding to and activating the receptors. The indole ring has been evaluated at all positions by the effect of substitutions as seen in figure 4. Each position is further explained below:
The melatonin receptors consist of proteins around 40 kDa each. The MT1 receptor encodes 350 amino acids and the MT2 encodes 362 amino acids. The binding of melatonin and its analogues to the receptors is not fully known. The binding space for melatonin and analogues on the MT1 receptor is smaller than on the MT2. Investigations usually focus on two binding pockets, for the two side-chains. The binding pocket of the 5-methoxy group is more investigated than the other pocket. Researchers agree that the oxygen in the group binds to histidine
(His) residues in transmembrane 5 (TM5) domain of the receptor with a hydrogen bond; His195 in MT1 and His208 in MT2. Another amino acid, valine
192 (Val), also participates in the binding of the 5-methoxy group by binding to the methyl portion of the group.
The binding of the N-acetyl group is more complex and less known. The important amino acids in the binding pocket for this group differ between the two receptors. Serine
s, Ser110 and Ser114, in the TM3 domain seem to be important for binding to the MT1 receptor. However, aspargine 175 (Asn) in the TM4 domain is likely to be important for the MT2 receptor. The aromatic ring system in melatonin and analogues most likely contributes some binding affinity by binding to aromatic rings of the amino acids phenylalanine
(Phe) and tryptophan
(Trp) in the receptor. The bonds that form are van der Waals interactions. The N-acetyl binding and binding pocket, binding of the ring system and important domains are somewhat known and need further investigation.
was developed by Takeda Pharmaceutical Company
and approved in the United States 2005. Agomelatine was developed by the pharmaceutical company Servier and approved in Europe 2009. Two melatonin agonists have received orphan drug designation and are going through clinical trials in the United States: Tasimelteon and TIK-301. Tasimelteon is being developed by Vanda Pharmaceuticals and completed the phase III trial in 2010.
Originally TIK-301 was developed by Eli Lilly and Company
and called LY-156,735, it wasn´t until July 2007 that Tikvah Pharmaceuticals took over the development and named it TIK-301. It is now in phase II trials and has been since 2002.
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Melatonin
Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...
that bind to and activate the melatonin receptor
Melatonin receptor
A melatonin receptor is a G protein-coupled receptor which binds melatonin.Three types of melatonin receptor have been cloned. The MT1 and MT2 receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype MT3 has been identified in amphibia and...
. Agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
s of the melatonin receptor have a number of therapeutic applications including treatment of sleep disorders and depression. The discovery and development of melatonin receptor agonists was motivated by the need for more potent analogues than melatonin
Melatonin
Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...
, with better pharmacokinetics
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
and longer half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
. Melatonin receptor agonists are analogues of melatonin and were developed with the melatonin structure as a model.
The melatonin receptors are G protein-coupled receptors and are expressed in various tissues of the body. There are two subtypes of the receptor in humans, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). Melatonin and melatonin receptor agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
s, on market or in clinical trials, all bind to and activate both receptor types. The binding of the agonists to the receptors has been investigated for over two decades or since 1986. It is somewhat known, but still not fully understood. When melatonin receptor agonists bind to and activate their receptors it causes numerous physiological processes.
History
In 1917 McCord and Allen discovered melatonin itself. Just over 40 years later, in 1958, Aaron B. LernerAaron B. Lerner
Aaron Bunsen Lerner was an American physician, researcher and professor. Born in 1920 in Minneapolis, he received his medical degree and a PhD in chemistry from the University of Minnesota in 1945. After teaching at the universities of Michigan and Oregon, he joined the Yale University School of...
and his colleagues isolated the substance N-acetyl-5-methoxytryptamine and named it melatonin. High-affinity melatonin binding sites were pharmacologically characterized in the bovine brain in 1979. The first melatonergic receptor was cloned from melanophores of Xenopus laevis in the 1990s. In 1994 the melatonin receptors were characterized and cloned in the human being. There has been a constant growth in the field of melatonin and melatonin analogues since the 1980s. In 2005 ramelteon
Ramelteon
Ramelteon, marketed as Rozerem by Takeda Pharmaceuticals North America, is the first in a new class of sleep agents that selectively binds to the MT1 and MT2 receptors in the suprachiasmatic nucleus , instead of binding to GABA A receptors, such as with drugs like zolpidem, eszopiclone, and...
(Rozerem®) was the first melatonin agonist to be approved in the United States (US), indicated for insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
treatment in adults which is characterized as difficulty with falling asleep. Melatonin in the form of the timed release Circadin® was approved in 2007 in Europe (EU) for use as a short-term treatment, in patients 55 years or older, for primary insomnia (poor quality of sleep). Products containing melatonin are available as a dietary supplement in the United States and Canada. In 2009 agomelatine (Valdoxan®, Melitor®, Thymanax®) was also approved in Europe and is indicated for the treatment of major depressive disorder in adults. Tasimelteon
Tasimelteon
Tasimelteon is a drug which is under development for the treatment of insomnia and other sleep disorders. It is a selective agonist for the melatonin receptors MT1 and MT2 in the suprachiasmatic nucleus of the brain, similar to older drugs such as ramelteon...
completed the phase III clinical trial in the United States for primary insomnia in 2010. The Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) granted tasimelteon orphan drug
Orphan drug
An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
designation status for blind individuals without light perception with non-24-hour sleep-wake disorder
Non-24-hour sleep-wake syndrome
Non-24-hour sleep-wake syndrome is a chronic circadian rhythm sleep disorder, classified within Chapter VI, Diseases of the Nervous System, in the ICD-10. It can be defined as "a chronic steady pattern comprising one- to two-hour daily delays in sleep onset and wake times in an individual living...
in January the same year. TIK-301 (PD-6735, LY-156,735
LY-156,735
LY-156735 is a melatonin MT1 and MT2 agonist which is under development for the treatment of insomnia and other sleep disorders....
) has been in phase II clinical trial in the United States since 2002. The FDA granted TIK-301 orphan drug designation in May 2004, to use as a treatment for circadian rhythm sleep disorder
Circadian rhythm sleep disorder
Circadian rhythm sleep disorders are a family of sleep disorders affecting, among other things, the timing of sleep. People with circadian rhythm sleep disorders are unable to sleep and wake at the times required for normal work, school, and social needs. They are generally able to get enough sleep...
in blind individuals without light perception and individuals with tardive dyskinesia
Tardive dyskinesia
Tardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
.
Melatonin receptors
In humans there are two subtypes of melatonin receptors, MT1Melatonin receptor 1A
Melatonin receptor type 1A is a protein that in humans is encoded by the MTNR1A gene.-Further reading:...
and MT2
Melatonin receptor 1B
Melatonin receptor 1B, also known as MTNR1B, is a protein that in humans is encoded by the MTNR1B gene.-Function:This gene encodes the MT2 protein, one of two high-affinity forms of a receptor for melatonin, the primary hormone secreted by the pineal gland. This gene product is an integral membrane...
. They are G protein-coupled receptors and are expressed in various tissues of the body, together or singly. MT1 receptors are expressed in many regions of the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS): suprachiasmatic nucleus
Suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms...
of the hypothalamus (SNC), hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
, cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
, central dopaminergic pathways
Dopaminergic pathways
Dopaminergic pathways are neural pathways in the brain which transmit the neurotransmitter dopamine from one region of the brain to another.The neurons of the dopaminergic pathways have axons which run the entire length of the pathway...
, ventral tegmental area and nucleus accumbens
Nucleus accumbens
The nucleus accumbens , also known as the accumbens nucleus or as the nucleus accumbens septi , is a collection of neurons and forms the main part of the ventral striatum...
. MT1 is also expressed in the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
, ovary
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...
, testis, mammary gland
Mammary gland
A mammary gland is an organ in mammals that produces milk to feed young offspring. Mammals get their name from the word "mammary". In ruminants such as cows, goats, and deer, the mammary glands are contained in their udders...
, coronary circulation
Coronary circulation
Coronary circulation is the circulation of blood in the blood vessels of the heart muscle . The vessels that deliver oxygen-rich blood to the myocardium are known as coronary arteries...
and aorta
Aorta
The aorta is the largest artery in the body, originating from the left ventricle of the heart and extending down to the abdomen, where it branches off into two smaller arteries...
, gallbladder
Gallbladder
In vertebrates the gallbladder is a small organ that aids mainly in fat digestion and concentrates bile produced by the liver. In humans the loss of the gallbladder is usually easily tolerated....
, liver, kidney, skin and the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. MT2 receptors are expressed mainly in the CNS, also in the lung, cardiac, coronary and aortic tissue, myometrium
Myometrium
The myometrium is the middle layer of the uterine wall, consisting mainly of uterine smooth muscle cells , but also of supporting stromal and vascular tissue...
and granulosa cells, immune cells, duodenum
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
and adipocytes.
Mechanism of action
The binding of melatonin to melatonin receptors activates a few signaling pathways. MT1 receptor activation inhibits the adenylyl cyclase and its inhibition causes a rippling effect of non activation; starting with decreasing formation of cyclic adenosine monophosphateCyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
(cAMP), and then progressing to less protein kinase A (PKA) activity, which in turn hinders the phosphorilation of cAMP responsive element-binding protein (CREB binding protein
CREB binding protein
CREB-binding protein, also known as CREBBP or CBP, is a protein that in humans is encoded by the CREBBP gene.The CREB protein carries out its function by activating transcription, where interaction with transcription factors is managed by one or more of p300 domains: the nuclear receptor...
) into P-CREB. MT1 receptors also activate phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
(PLC), affect ion channels and regulate ion flux inside the cell. The binding of melatonin to MT2 receptors inhibits adenylyl cyclase which decreases the formation of cAMP. As well it hinders guanylyl cyclase and therefore the forming of cyclic guanosine monophosphate
Cyclic guanosine monophosphate
Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...
(cGMP). Binding to MT2 receptors probably affects PLC which increases protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
(PKC) activity. Activation of the receptor can lead to ion flux inside the cell.
When melatonin receptor agonists activate their receptors it causes numerous physiological processes. MT1 and MT2 receptors may be a target for the treatment of circadian and non circadian sleep disorders because of their differences in pharmacology and function within the SCN. SCN is responsible for maintaining the 24 hour cycle which regulates many different body functions ranging from sleep to immune functions. Melatonin receptors have been identified in the cardiovascular system. Number of animal studies point to a dual role of melatonin in the vasculature. Activation of MT1 receptors mediates vasoconstriction and the activation of MT2 receptors mediates vasodilation. Melatonin is involved in regulating immune responses in both human and animals through activation of both MT1 and MT2 receptors. MT1 and MT2 receptors are widespread in the eye and are involved in regulating aqueous humor secretion, which is important for glaucoma
Glaucoma
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
, and in phototransduction. This is not a complete list since many of the possible processes need further confirmation.
Drug design and development
Receptors and the structure of melatonin are known. Therefore researchers started to investigate modulations of the core structure to develop better agonists then melatonin; more potent, with better pharmacokinetics and longer half-life. TIK-301 (figure 4) is an agonist of the early classes. It is very similar to melatonin and has made it to clinical trials. This led to further researches on the molecule, mainly substitution of the aromatic ring. Various modulations showed promising activity, specially the naphthaleneNaphthalene
Naphthalene is an organic compound with formula . It is a white crystalline solid with a characteristic odor that is detectable at concentrations as low as 0.08 ppm by mass. As an aromatic hydrocarbon, naphthalene's structure consists of a fused pair of benzene rings...
ring which is present in agomelatine (figure 4). Other ring systems have also showed melatonin agonist activity. Amongst them are indane
Indane
Indane or indan is a hydrocarbon petrochemical compound.-Derivatives:Derivatives include compounds such as 1-methyl-indane and 2-methyl-indane , 4-methyl-indane and 5-methyl-indane , various dimethyl-indanes, and various pharmaceutical derivatives...
which is present in ramelteon (figure 4) and the ring system of tasimelteon (figure 4).
Structure-activity relationship (SAR)
The general structure of melatonin is the indoleIndole
Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an...
ring with methoxy
Methoxy
In chemistry , methoxy refers to the functional group consisting of a methyl group bound to oxygen. This alkoxy group has the formula O–CH3.The word is used in organic nomenclature usually to describe an ether...
group in position 5 (5-methoxy group) and acylaminoethyl side-chain in position 3. The two side-chains are important for binding to and activating the receptors. The indole ring has been evaluated at all positions by the effect of substitutions as seen in figure 4. Each position is further explained below:
- Position 1 (R1): Possible to substitute with small groups like methyl without little changes in binding affinity. Bulky groups lower binding affinity and intrinsic activityIntrinsic activityIntrinsic activity or efficacy refers to the relative ability of a drug-receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind to its molecular target, and the EC50, which is a measure of the...
. - Position 2 (R2): Molecules like iodine (I) and bromine (Br) and phenyl groupPhenyl groupIn organic chemistry, the phenyl group or phenyl ring is a cyclic group of atoms with the formula C6H5. Phenyl groups are closely related to benzene. Phenyl groups have six carbon atoms bonded together in a hexagonal planar ring, five of which are bonded to individual hydrogen atoms, with the...
s lead to agonists with higher binding affinity or approximately ten-fold. - Position 3 (R3): The acylaminoethyl side-chain is important, as mentioned before. In this position it is possible to control agonist and antagonist activity.
- Position 4 (R4): Often involved in ring closure in melatonin agonists, although this position has been poorly investigated.
- Position 5 (R5): The methoxy group is important, as mentioned before. Substitution with halogens, such as chlorine (Cl) and bromine (Br) has shown lower binding affinity. Moving the methoxy group to other positions on the indole ring, e.g. 4, 6 or 7, leads to lower binding affinity.
- Position 6 (R6): Substitution leads to lower binding affinity, but this position is important for the pharmacokinetics. The main metabolite in vivo is 6-hydroxymelatonin.
- Position 7 (R7): Introduction of groups at this position generally leads to lower binding affinity.
- Position β (Rβ): Possible to substitute with small groups like methyl without little changes in binding affinity. Bulkier groups lower binding affinity.
Binding and pharmacophore
2-iodomelatonin was synthesized in 1986 and its radioligand, 2-[125I]-melatonin, has been useful in finding cellular targets of melatonin. Though the melatonin receptor wasn’t characterized and cloned in the human being until 1994 it was possible to start carrying out binding studies in various tissues before that time. As mentioned in the structure-activity relationship chapter above, certain groups are important for the activity. The most important groups are the 5-methoxy group and the acylaminoethyl side-chain, because they bind to and activate the receptors. The –NH group of the indole ring is not important for binding and activation. Therefore it is possible to replace it with other aromatic ring systems. The aromatic ring and the ethyl side-chain hold the correct distance between those two groups. The correct distance is the key to good binding and more important than what type of aromatic ring system the analogue contains. Therefore it is possible to use different ring systems in melatonin receptor analogues, if the distance is right.The melatonin receptors consist of proteins around 40 kDa each. The MT1 receptor encodes 350 amino acids and the MT2 encodes 362 amino acids. The binding of melatonin and its analogues to the receptors is not fully known. The binding space for melatonin and analogues on the MT1 receptor is smaller than on the MT2. Investigations usually focus on two binding pockets, for the two side-chains. The binding pocket of the 5-methoxy group is more investigated than the other pocket. Researchers agree that the oxygen in the group binds to histidine
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...
(His) residues in transmembrane 5 (TM5) domain of the receptor with a hydrogen bond; His195 in MT1 and His208 in MT2. Another amino acid, valine
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...
192 (Val), also participates in the binding of the 5-methoxy group by binding to the methyl portion of the group.
The binding of the N-acetyl group is more complex and less known. The important amino acids in the binding pocket for this group differ between the two receptors. Serine
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:...
s, Ser110 and Ser114, in the TM3 domain seem to be important for binding to the MT1 receptor. However, aspargine 175 (Asn) in the TM4 domain is likely to be important for the MT2 receptor. The aromatic ring system in melatonin and analogues most likely contributes some binding affinity by binding to aromatic rings of the amino acids phenylalanine
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) and tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
(Trp) in the receptor. The bonds that form are van der Waals interactions. The N-acetyl binding and binding pocket, binding of the ring system and important domains are somewhat known and need further investigation.
Current status
There are two melatonin agonists on the market today (November 2010); ramelteon (Rozerem®) and agomelatine (Valdoxan®, Melitor®, Thymanax®). RamelteonRamelteon
Ramelteon, marketed as Rozerem by Takeda Pharmaceuticals North America, is the first in a new class of sleep agents that selectively binds to the MT1 and MT2 receptors in the suprachiasmatic nucleus , instead of binding to GABA A receptors, such as with drugs like zolpidem, eszopiclone, and...
was developed by Takeda Pharmaceutical Company
Takeda Pharmaceutical Company
is the largest pharmaceutical company in Japan and Asia and a top 15 pharmaceutical company. The company has over 19,000 employees worldwide and achieved $15.7 billion USD in revenue during the 2008 fiscal year...
and approved in the United States 2005. Agomelatine was developed by the pharmaceutical company Servier and approved in Europe 2009. Two melatonin agonists have received orphan drug designation and are going through clinical trials in the United States: Tasimelteon and TIK-301. Tasimelteon is being developed by Vanda Pharmaceuticals and completed the phase III trial in 2010.
Originally TIK-301 was developed by Eli Lilly and Company
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...
and called LY-156,735, it wasn´t until July 2007 that Tikvah Pharmaceuticals took over the development and named it TIK-301. It is now in phase II trials and has been since 2002.
| Table 1. Several characteristics of approved receptor agonists and orphan drug agonists | |||||
| Circadin | Ramelteon | Agomelatine | Tasimelteon | TIK-301 | |
|---|---|---|---|---|---|
| Binding affinity | - | MT1: Ki = 0.014 nM MT2: Ki = 0.045 nM |
MT1: Ki = 0.062 nM MT2: Ki = 0.268 nM 5-HT2C: IC50 = 270 nM* |
MT1: Ki = 0.35 nM MT2: Ki = 0.17 nM |
MT1: Ki = 0.081nM MT2: Ki = 0.042 nM |
| Bioavailability | 15% | < 2% | < 5% | - | - |
| Half-life | 40-50 min 3.5-4 h (terminal) |
1-2 h | 1-2 h | - | - |
| Protein binding | 60% | 82% | 95% | - | - |
| Volume of distribution | - | 73.6 L | 35 L | - | - |
| Company | Neurim Pharmaceuticals | Takeda Pharmaceutical Company | Servier | Vanda Pharmaceuticals | Tikvah Pharmaceuticals |
| *Serotonin antagonist | |||||
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Many major physiological processes depend on regulation of proteolytic enzyme activity and there can be dramatic consequences when equilibrium between an enzyme and its substrates is disturbed. In this prospective, the discovery of small-molecule ligands, like protease inhibitors, that can modulate...
Discovery and development of non-nucleoside reverse transcriptase inhibitors
Discovery and development of non-nucleoside reverse transcriptase inhibitors
Non-nucleoside reverse-transcriptase inhibitors are antiretroviral drugs used in the treatment of human immunodeficiency virus . NNRTIs inhibit reverse transcriptase , an enzyme that controls the replication of the genetic material of HIV...
Cannabinoid receptor antagonist
Cannabinoid receptor antagonist
The discovery of the endogenous cannabinoid system led to the development of CB1 receptor antagonists. The first cannabinoid receptor "antagonist," rimonabant, was described in 1994. Rimonabant blocks the CB1 receptor selectively and it has been shown to decrease food intake and regulate...
Development of dipeptidyl peptidase-4 inhibitors
Development of dipeptidyl peptidase-4 inhibitors
Dipeptidyl peptidase-4 inhibitors are enzyme inhibitors that inhibit the enzyme dipeptidyl peptidase-4 and are a potent treatment for type 2 diabetes...
Discovery and development of Bcr-Abl tyrosine kinase inhibitors
Discovery and Development of Proton Pump Inhibitors
Discovery and development of proton pump inhibitors
Proton pump inhibitors block the gastric Hydrogen potassium ATPase and inhibit gastric acid secretion. These drugs have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease and peptic ulcer disease.-History:Evidence emerged by the end of the...