Discovery and development of dual serotonin and norepinephrine reuptake inhibitors
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Discovery and development of dual serotonin and norepinephrine reuptake inhibitors
Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant drugs used in the treatment of major depressive disorder (MDD). SNRIs are potent inhibitors of serotonin
(5-Hydroxytryptamine, 5-HT) and norepinephrine
(NE, noradrenalin) reuptake
. These neurotransmitters are known to play an important role in mood. The human serotonin transporter
(SERT) and norepinephrine transporter
(NET) are membrane proteins that are responsible for the reuptake of serotonin and norepinephrine. Balanced dual inhibition of monoamine reuptake can possibly offer advantages over other antidepressants drugs by treating a wider range of symptoms.
SNRIs are second-generation agents, such as selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitor
s (NRIs). Over the past two decades, second-generation agents have gradually replaced first-generation agents, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) as the drugs of choice for the treatment of MDD. This is mainly because of their improved tolerability and safety profile.
, a antimycobacterial
agent, was discovered to have psychoactive properties while researched as a possible treatment for tuberculosis
. Researchers noted that patients given iproniazid became cheerful, more optimistic, and more physically active. Soon after its development, iproninazid and related substances were shown to slow enzymatic breakdown of norepinephrine, serotonin and dopamine
via inhibition of mitochondrial enzyme monoamine oxidase. For this reason this class of drugs became known as MAOIs. During this time development of distinctively different antidepressant agents was also researched. Imipramine
became the first clinically useful TCA. Imipramine was found to affect numerous neurotransmitter systems and to block reuptake of norepinephrine and serotonin from the synapse
, therefore increasing the levels of these neurotransmitters. Use of MAOIs and TCAs gave major advances in treatment of depression but their use was limited by unpleasant side effects
and significant safety and toxicity
issues .
Throughout the 1960s and 1970s the catecholamine
hypothesis of emotion and its relation to depression was of wide interest and that the decreased levels of certain neurotransmitters, such as norepinephrine, serotonin, and dopamine might play a role in the pathogenesis
of depression. This led to the development of fluoxetine
, the first SSRI. The improved safety and tolerability profile of the SSRIs in patients with MDD, compared with TCAs and MAOIs, represented yet another important advance in the treatment of depression.
Since the late 1980s SSRIs have dominated the antidepressant drug market. Today there is increased interest in antidepressant drugs with broader mechanisms of action that may offer improvements in efficacy and fewer adverse effects. In 1993 a new drug was introduced to the US market called venlafaxine
, a serotonin-norepinephrine reuptake inhibitor . Venlafaxine was the first compound described in a new class of antidepressive substances called phenylethylamines. These substances are unrelated to TCA and other SSRIs. Venlafaxine blocks the neuronal reuptake of serotonin, noradrenaline, and, to a lesser extent, dopamine
in the central nervous system
. In contrast with several other antidepressant drugs, venlafaxine can induce a rapid onset of action mainly due to a subsequent norepinephrine reuptake inhibition. See timeline in figure 1.
(Efexor®, Effexor®) was the first drug described in the class of SNRIs. Venlafaxine was approved by the Food and Drug Administration
(FDA) in the US in 1993 for the management of treatment-resistant depression (TRD). Venlafaxine with extended-release was also introduced to the US market for the treatment of generalized anxiety disorder (GAD) as well as chronic pain
syndromes.
Sibutramine
(Meridia®, Reductil®) is used in the treatment of obesity
. Sibutramine was approved by the FDA in 1998 and was then a new class of medication
. Sibutramine was then the first drug for the treatment of obesity to be approved in 30 years.
Duloxetine
(Cymbalta®, Ariclaim®, Xeristar®, Yentreve®) was the second SNRI approved by the FDA in 2004. Duloxetine is used in the treatment of MDD and fibromyalgia
.
Desvenlafaxine
(Pristiq®) is the active metabolite
of venlafaxine. Desvenlafaxine is used in the treatment of MDD in adults. Desvenlafaxine was approved by the FDA in 2008 and was then the third approved SNRI.
Milnacipran
(Savella®, Ixel®, Dalcipran®, Toledomin®) was approved by the FDA in 2009 for the treatment of pain and multiple symptoms associated with fibromyalgia syndrome. Milnacipran is also used in the treatment of MDD. See timeline of approved SNRIs in figure 2.
of depression. Symptoms are thought to appear because concentrations of neurotransmitters for example norepinephrine and serotonin are insufficient . Medications to treat symptoms of depression effect the transmission of serotonin, norepinephrine and/or dopamine . Older and more unselective antidepressants like TCAs and MAOIs, act by inhibiting the reuptake or metabolism
, of norepinephrine and/or serotonin in the brain which concludes higher neurotransmitters concentrations . Antidepressants that have dual mechanisms of action, inhibit both serotonin and norepinephrine reuptake, in some cases with weak effect on dopamine reuptake .
Antidepressants have effects on variable neuronal receptors like muscarinic-cholinergic, α1- and α2-adrenergic, and H1-histaminergic receptors, and sodium channels in the cardiac muscle
, leading to decreased cardiac conduction and cardiotoxicity
. Selectivity of antidepressant agents are based on the neurotransmitters that are thought to influence symptoms of depression .
Drugs that selectively block the reuptake of serotonin and/or norepinephrine have shown to be effective in treating depression and are better tolerated than TCAs. TCAs have comprehensive effects on various neurotransmitters receptors, which leads to lack of tolerability and increased risk of toxicity
TCAs were the first medications that had dual mechanism of action. The mechanism of action of tricyclic secondary amine antidepressants is only partly understood. TCAs have dual inhibition effects on norepinephrine reuptake transporters and serotonin reuptake transporters.
Increased norepinephrine and serotonin concentrations are obtained by inhibiting both of these transporter proteins. TCAs have substantially more affinity for norepinephrine reuptake proteins than the SSRIs. This is because of a formation of secondary amine TCA metabolites .
In addition, the TCAs interact with adrenergic receptors. This interaction seems to be critical for increased availability of norepinephrine in or near the synaptic clefts. Actions of imipramine-like tricyclic antidepressants have complex, secondary adaptions to their initial and sustained actions as inhibitors of norepinephrine transport and variable blockade of serotonin transport. Norepinephrine interacts with postsynaptic α- and β-adrenergic receptor subtypes and presynaptic α2-autoreceptors. The α2-receptors include presynaptic autoreceptors which limit the neurophysiological activity of noradrenergic neurons in the central nervous system
. Formation of norepinephrine is reduced by autoreceptors through the ratelimiting enzyme tyrosine hydroxylase
, by decreasing the expression of cyclic AMP-mediated phosphorylation
-activation of the enzyme
. α2-receptors also cause decreased intracellular cyclic AMP expression which is resulted in smooth muscle
relaxation or decreased secretion . TCAs activate a negative-feedback mechanism through its effects on presynaptic receptor mediation. Probable explanation of effects on decreased neurotransmitter release is that as the receptors activate, inhibition of neurotransmitter release occurs, including suppression of voltage-gated Ca2+ currents and activation of G protein-coupled receptor-operated K+ currents. Repeated exposure of agents with this type of mechanism leads to inhibition of neurotransmitter release. However, repeated administration of TCAs finally results in decreased responses of α2-receptors.
This desensitization
of these respones may be caused due to increased exposure to the endogen norepinephrine or from prolonged occupation of the norepinephrine transport itself caused by allosteric effect. This adaptation allows the presynaptic synthesis and secration of norepinephrine to return to, or even exceed, normal levels of norepinephrine in the synaptic clefts. Overall inhibition of norepinephrine reuptake induced by TCAs, lead to decreased rates of neuron firing (mediated through α2-autoreceptors), metabolic activity, and release of neurotransmitters . For schematic overview see figure 3.
TCAs do not block dopamine transport but might facilitate dopamine effects indirectly by transport-inhibition of dopamine into noreadrenergic terminals in cerebral cortex
. Because of multiple effects on different receptors, TCAs have poor tolerability which could result in adverse effects and increased risk of toxicity .
system regulates the uptake of tryptophan
across the blood-brain barrier
. Serotonergic pathways are classified into two main ways in the brain; the ascending projections from the medial and dorsal raphe and the descending projections from the caudal raphe into the spinal cord
. The reuptake blocking of SSRIs into the presynaptic terminal results in increased concentration of serotonin in the synaptic cleft, just like the TCAs, but with much less additional effects. Altering the serotonin concentrations to higher levels influence symptoms of anxiety which coexist with depression, leading to improvement of depression symptoms .
Assays have shown that selective NRIs have insignificant penchant for muscarinic-cholinergic, α1- and α2-adrenergic or H1-histaminergic receptors .
Between the nontricyclic SNRIs there are several important differences that are based on pharmacokinetics, metabolism to active metabolites, inhibition of CYP isoforms, effect of drug-drug interactions and the half-life
of the nontricyclic SNRIs .
Combination of mechanisms of action in a single active agent is an important development in psychopharmacology
.
contain an aryloxypropanamine scaffold (see figure 4). This structural motif has potential for high affinity binding to biogenic amine transports . Drugs containing an aryloxypropanamine scaffold have selectivity profile for norepinephrine and serotonin transporters that depends on the substitution pattern of the aryloxy ring. Selective NRIs contain a substituent in 2‘- position of the aryloxy ring but SSRIs contain a substituent
in 4‘- position of the aryloxy ring. Atomoxetine, nisoxetine
and reboxetine all have a substitution group in the 2´-position and are selective NRIs while compounds that have a substitution group in the 4´-position like fluoxetine and paroxetine
are SSRIs. Drugs like duloxetine contain a phenyl group
fused at the 2´ and 3´-positions. Duloxetine has therefore dual selective norepinephrine and serotonin reuptake inhibitory effects and has similar potencies for the both transporters . The nature of the aromatic substituent R has a significant influence on the activity and selectivity of the compounds as inhibitors of the serotonin or the norepinephrine transporters . See figure 5.
of milnacipran derivatives is still largely unclear . The conformation of milnacipran is an important part of its pharmacophore. Changing the SAR in milnacipran changes the stereochemistry
of the compound and affects the norepinephrine and serotonin concentration. Milnacipran is marketed as a racemic mixture. Effects of milnacipran resides in the 1S,2R-isomer and substitution of the phenyl group in the 1S,2R isomer has negative impact on norepinephrine concentration . Milnacipran has low molecular weight and low lipophilicity. Because of these properties milnacipran exhibits almost ideal pharmacokinetics
in humans such as high bioavailability
, low inter-subject variability, limited liver enzyme
interaction, moderate tissue distribution and a reasonably long elimination half-life. Milnacipran´s lack of drug-drug interactions via cytochrome P450 enzymes is thought to be an attractive feature because many of the central nervous system drugs are highly lipophilic and are mainly eliminated by liver enzymes .
ring system. Some studies have been made where the oxygen in reboxetine is replaced by sulfur
to give arylthiomethyl morpholine. Some of the arylthiomethyl morpholine derivatives maintain potent levels of serotonin and norepinephrine reuptake inhibition. Dual serotonin and norepinephrine reuptake inhibition resides in different enantiomers for arylthiomethyl morpholine scaffold . Possible drug candidates with dual serotonin and norepinephrine reuptake inhibitory activity have also been derived from piperazine, 3-amino-pyrrolidine and benzylamine templates .
seem to be less expensive than other drugs for example in the UK. Further research is needed to examine whether larger differences between classes of antidepressant drugs might exist in specific MDD sub-populations or for specific MDD symptoms.
Data from clinical trials have indicated that SNRIs might have pain relieving properties. The pain perception and transmission in the central nervous system have not been fully elucidated however, extensive data support a role of serotonin and norepinephrine in the modulation of pain. This is also supported by data from clinical trials in humans in which antidepressants have been shown to reduce pain and functional impairment in central and neuropathic pain conditions. This property of SNRIs might be used to reduce doses of other pain relieving medication and lower frequency of limited efficacy, safety and tolerability issues.
Clinical research data have shown in patients with GAD that the SNRI duloxetine is significantly more effective than placebo in reducing painful physical symptoms of GAD after short-term and long-term treatment. Findings suggested that painful physical symptoms reoccur with relapsing that indicate a need for ongoing treatment in patients with GAD and concurrent painful physical symptoms.
is the enantiomer of milnacipran. Like milnacipran, levomilnacipran is a selective SNRI. Levomilnacipran is currently under development for the treatment of MDD.
Bicifadine
is a SNRI. Bicifadine is being developed for the treatment of acute
and chronic pain. Clinical research have shown that bicifadine is effective in the treatment of acute dental pain and bunionectomy pain. Bicifadine has also been reported to be as effective as the standard of care in reducing chronic lower back pain.
5-HT: Serotonin - NE: Norepinephrine - D: Dopamine - NA: Not available
Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant drugs used in the treatment of major depressive disorder (MDD). SNRIs are potent inhibitors of serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
(5-Hydroxytryptamine, 5-HT) and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
(NE, noradrenalin) reuptake
Reuptake
Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse....
. These neurotransmitters are known to play an important role in mood. The human serotonin transporter
Serotonin transporter
The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
(SERT) and norepinephrine transporter
Norepinephrine transporter
The norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....
(NET) are membrane proteins that are responsible for the reuptake of serotonin and norepinephrine. Balanced dual inhibition of monoamine reuptake can possibly offer advantages over other antidepressants drugs by treating a wider range of symptoms.
SNRIs are second-generation agents, such as selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitor
Norepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
s (NRIs). Over the past two decades, second-generation agents have gradually replaced first-generation agents, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) as the drugs of choice for the treatment of MDD. This is mainly because of their improved tolerability and safety profile.
History
In 1952 iproniazidIproniazid
Iproniazid is a hydrazine drug used as an antidepressant. It acts as an irreversible and nonselective monoamine oxidase inhibitor . Though it has been widely discontinued in most of the world, it is still used in France.- History :Iproniazid was the first antidepressant ever marketed...
, a antimycobacterial
Antimycobacterial
An antimycobacterial is a type of drug used to treat Mycobacteria infections.Types include:* Tuberculosis treatments* Leprostatic agents...
agent, was discovered to have psychoactive properties while researched as a possible treatment for tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
. Researchers noted that patients given iproniazid became cheerful, more optimistic, and more physically active. Soon after its development, iproninazid and related substances were shown to slow enzymatic breakdown of norepinephrine, serotonin and dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
via inhibition of mitochondrial enzyme monoamine oxidase. For this reason this class of drugs became known as MAOIs. During this time development of distinctively different antidepressant agents was also researched. Imipramine
Imipramine
Imipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
became the first clinically useful TCA. Imipramine was found to affect numerous neurotransmitter systems and to block reuptake of norepinephrine and serotonin from the synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
, therefore increasing the levels of these neurotransmitters. Use of MAOIs and TCAs gave major advances in treatment of depression but their use was limited by unpleasant side effects
Side Effects
Side Effects is an anthology of 17 comical short stories written by Woody Allen between 1975 and 1980, all but one of which were previously published in, variously, The New Republic, The New York Times, The New Yorker, and The Kenyon Review. It includes Allen's 1978 O...
and significant safety and toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
issues .
Throughout the 1960s and 1970s the catecholamine
Catecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...
hypothesis of emotion and its relation to depression was of wide interest and that the decreased levels of certain neurotransmitters, such as norepinephrine, serotonin, and dopamine might play a role in the pathogenesis
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
of depression. This led to the development of fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
, the first SSRI. The improved safety and tolerability profile of the SSRIs in patients with MDD, compared with TCAs and MAOIs, represented yet another important advance in the treatment of depression.
Since the late 1980s SSRIs have dominated the antidepressant drug market. Today there is increased interest in antidepressant drugs with broader mechanisms of action that may offer improvements in efficacy and fewer adverse effects. In 1993 a new drug was introduced to the US market called venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
, a serotonin-norepinephrine reuptake inhibitor . Venlafaxine was the first compound described in a new class of antidepressive substances called phenylethylamines. These substances are unrelated to TCA and other SSRIs. Venlafaxine blocks the neuronal reuptake of serotonin, noradrenaline, and, to a lesser extent, dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
in 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...
. In contrast with several other antidepressant drugs, venlafaxine can induce a rapid onset of action mainly due to a subsequent norepinephrine reuptake inhibition. See timeline in figure 1.
Overview of SNRIs
VenlafaxineVenlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
(Efexor®, Effexor®) was the first drug described in the class of SNRIs. Venlafaxine was approved by 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) in the US in 1993 for the management of treatment-resistant depression (TRD). Venlafaxine with extended-release was also introduced to the US market for the treatment of generalized anxiety disorder (GAD) as well as chronic pain
Chronic pain
Chronic pain has several different meanings in medicine. Traditionally, the distinction between acute and chronic pain has relied upon an arbitrary interval of time from onset; the two most commonly used markers being 3 months and 6 months since the initiation of pain, though some theorists and...
syndromes.
Sibutramine
Sibutramine
Sibutramine is an oral anorexiant. Until 2010 it was marketed and prescribed as an adjunct in the treatment of exogenous obesity along with diet and exercise...
(Meridia®, Reductil®) is used in the treatment of obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
. Sibutramine was approved by the FDA in 1998 and was then a new class of medication
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
. Sibutramine was then the first drug for the treatment of obesity to be approved in 30 years.
Duloxetine
Duloxetine
Duloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine for generalized anxiety disorder...
(Cymbalta®, Ariclaim®, Xeristar®, Yentreve®) was the second SNRI approved by the FDA in 2004. Duloxetine is used in the treatment of MDD and fibromyalgia
Fibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
.
Desvenlafaxine
Desvenlafaxine
Desvenlafaxine , also known as O-desmethylvenlafaxine, is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class developed and marketed by Wyeth . Desvenlafaxine is a synthetic form of the major active metabolite of venlafaxine...
(Pristiq®) is the active metabolite
Active metabolite
- Prodrugs :Sometimes drugs are formulated deliberately so they will break down inside the body to form the active drug, these are called prodrugs. The reason for this may be because the drug is more stable during manufacture and storage as the prodrug form, or because the prodrug is better...
of venlafaxine. Desvenlafaxine is used in the treatment of MDD in adults. Desvenlafaxine was approved by the FDA in 2008 and was then the third approved SNRI.
Milnacipran
Milnacipran
Milnacipran is a serotonin–norepinephrine reuptake inhibitor used in the clinical treatment of fibromyalgia...
(Savella®, Ixel®, Dalcipran®, Toledomin®) was approved by the FDA in 2009 for the treatment of pain and multiple symptoms associated with fibromyalgia syndrome. Milnacipran is also used in the treatment of MDD. See timeline of approved SNRIs in figure 2.
Mechanism of action
Monoamines are connected to the pathophysiologyPathophysiology
Pathophysiology is the study of the changes of normal mechanical, physical, and biochemical functions, either caused by a disease, or resulting from an abnormal syndrome...
of depression. Symptoms are thought to appear because concentrations of neurotransmitters for example norepinephrine and serotonin are insufficient . Medications to treat symptoms of depression effect the transmission of serotonin, norepinephrine and/or dopamine . Older and more unselective antidepressants like TCAs and MAOIs, act by inhibiting the reuptake or metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
, of norepinephrine and/or serotonin in the brain which concludes higher neurotransmitters concentrations . Antidepressants that have dual mechanisms of action, inhibit both serotonin and norepinephrine reuptake, in some cases with weak effect on dopamine reuptake .
Antidepressants have effects on variable neuronal receptors like muscarinic-cholinergic, α1- and α2-adrenergic, and H1-histaminergic receptors, and sodium channels in the cardiac muscle
Cardiac muscle
Cardiac muscle is a type of involuntary striated muscle found in the walls and histologic foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle...
, leading to decreased cardiac conduction and cardiotoxicity
Cardiotoxicity
Cardiotoxicity is the occurrence of heart electrophysiology dysfunction or/and muscle damage. The heart becomes weaker and is not as efficient in pumping and therefore circulating blood...
. Selectivity of antidepressant agents are based on the neurotransmitters that are thought to influence symptoms of depression .
Drugs that selectively block the reuptake of serotonin and/or norepinephrine have shown to be effective in treating depression and are better tolerated than TCAs. TCAs have comprehensive effects on various neurotransmitters receptors, which leads to lack of tolerability and increased risk of toxicity
Tricyclic antidepressants
Increased norepinephrine and serotonin concentrations are obtained by inhibiting both of these transporter proteins. TCAs have substantially more affinity for norepinephrine reuptake proteins than the SSRIs. This is because of a formation of secondary amine TCA metabolites .
In addition, the TCAs interact with adrenergic receptors. This interaction seems to be critical for increased availability of norepinephrine in or near the synaptic clefts. Actions of imipramine-like tricyclic antidepressants have complex, secondary adaptions to their initial and sustained actions as inhibitors of norepinephrine transport and variable blockade of serotonin transport. Norepinephrine interacts with postsynaptic α- and β-adrenergic receptor subtypes and presynaptic α2-autoreceptors. The α2-receptors include presynaptic autoreceptors which limit the neurophysiological activity of noradrenergic neurons in 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...
. Formation of norepinephrine is reduced by autoreceptors through the ratelimiting enzyme tyrosine hydroxylase
Tyrosine hydroxylase
Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to dihydroxyphenylalanine . It does so using tetrahydrobiopterin as a coenzyme. DOPA is a precursor for dopamine, which, in turn, is a precursor for norepinephrine ...
, by decreasing the expression of cyclic AMP-mediated phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
-activation of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
. α2-receptors also cause decreased intracellular cyclic AMP expression which is resulted in smooth muscle
Smooth muscle
Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
relaxation or decreased secretion . TCAs activate a negative-feedback mechanism through its effects on presynaptic receptor mediation. Probable explanation of effects on decreased neurotransmitter release is that as the receptors activate, inhibition of neurotransmitter release occurs, including suppression of voltage-gated Ca2+ currents and activation of G protein-coupled receptor-operated K+ currents. Repeated exposure of agents with this type of mechanism leads to inhibition of neurotransmitter release. However, repeated administration of TCAs finally results in decreased responses of α2-receptors.
This desensitization
Desensitization
Desensitization can refer to:* Desensitization * Desensitization * Desensitization * Desensitization of explosives, see Phlegmatized...
of these respones may be caused due to increased exposure to the endogen norepinephrine or from prolonged occupation of the norepinephrine transport itself caused by allosteric effect. This adaptation allows the presynaptic synthesis and secration of norepinephrine to return to, or even exceed, normal levels of norepinephrine in the synaptic clefts. Overall inhibition of norepinephrine reuptake induced by TCAs, lead to decreased rates of neuron firing (mediated through α2-autoreceptors), metabolic activity, and release of neurotransmitters . For schematic overview see figure 3.
TCAs do not block dopamine transport but might facilitate dopamine effects indirectly by transport-inhibition of dopamine into noreadrenergic terminals in cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
. Because of multiple effects on different receptors, TCAs have poor tolerability which could result in adverse effects and increased risk of toxicity .
Selective serotonin reuptake inhibitors
Selective serotonin reuptake inhibitors (SSRIs) selectively inhibit the reuptake of serotonin and are a widely used group of antidepressants . With increased receptors selectivity compared to TCAs, undesired effects like poor tolerability are avoided . Serotonin is synthesized from an amino acid called L-tryptophan. Active transportActive transport
Active transport is the movement of a substance against its concentration gradient . In all cells, this is usually concerned with accumulating high concentrations of molecules that the cell needs, such as ions, glucose, and amino acids. If the process uses chemical energy, such as from adenosine...
system regulates the uptake of 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...
across the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
. Serotonergic pathways are classified into two main ways in the brain; the ascending projections from the medial and dorsal raphe and the descending projections from the caudal raphe into the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
. The reuptake blocking of SSRIs into the presynaptic terminal results in increased concentration of serotonin in the synaptic cleft, just like the TCAs, but with much less additional effects. Altering the serotonin concentrations to higher levels influence symptoms of anxiety which coexist with depression, leading to improvement of depression symptoms .
Selective norepinephrine reuptake inhibitors
There are two major regions in the brain where noradrenergic neurons are located. These regions are called locus coeruleus and the lateral tegmental. With administration of selective NRIs, neuronal activity in locus coeruleus region is induced because of increased concentration of norepinephrine in the synaptic cleft. This results in activation of α2-adrenoreceptors , as discussed in section 5.1.Assays have shown that selective NRIs have insignificant penchant for muscarinic-cholinergic, α1- and α2-adrenergic or H1-histaminergic receptors .
Dual serotonin and norepinephrine reuptake inhibitors
Agents with dual serotonin and norepinephrine reuptake inhibition (SNRIs) are sometimes called nontricyclic serotonin and norepinephrine reuptake inhibitors. Clinical studies suggest that compounds which increase the concentration in the synaptic cleft of both norepinephrine and serotonin are more successful than single acting agents in the treatment of depression. Dual reuptake inhibitors have low affinity at neuronal receptors of the other neurotransmitters which results in a low adverse effects, compared with the TCAs. Nontricyclic antidepressants have improved potency and onset action acceleration in antidepressant response than SSRI alone, which give the impression that synergism is an efficient property in mediating antidepressant activity.Between the nontricyclic SNRIs there are several important differences that are based on pharmacokinetics, metabolism to active metabolites, inhibition of CYP isoforms, effect of drug-drug interactions and the half-life
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...
of the nontricyclic SNRIs .
Combination of mechanisms of action in a single active agent is an important development in psychopharmacology
Psychopharmacology
Psychopharmacology is the scientific study of the actions of drugs and their effects on mood, sensation, thinking, and behavior...
.
Aryloxypropanamine scaffold
Atomoxetine, fluoxetine, duloxetine and reboxetineReboxetine
Reboxetine is a drug marketed as an antidepressant for use in the treatment of clinical depression, panic disorder and ADD/ADHD, developed by Pharmacia . Its mesylate salt is sold under tradenames including Edronax, Norebox, Prolift, Solvex, Davedax or Vestra...
contain an aryloxypropanamine scaffold (see figure 4). This structural motif has potential for high affinity binding to biogenic amine transports . Drugs containing an aryloxypropanamine scaffold have selectivity profile for norepinephrine and serotonin transporters that depends on the substitution pattern of the aryloxy ring. Selective NRIs contain a substituent in 2‘- position of the aryloxy ring but SSRIs contain a substituent
Substituent
In organic chemistry and biochemistry, a substituent is an atom or group of atoms substituted in place of a hydrogen atom on the parent chain of a hydrocarbon...
in 4‘- position of the aryloxy ring. Atomoxetine, nisoxetine
Nisoxetine
Nisoxetine is a drug which inhibits the reuptake of norepinephrine . It is a racemic compound with two isomers...
and reboxetine all have a substitution group in the 2´-position and are selective NRIs while compounds that have a substitution group in the 4´-position like fluoxetine and paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
are SSRIs. Drugs like duloxetine contain a phenyl group
Phenyl group
In 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...
fused at the 2´ and 3´-positions. Duloxetine has therefore dual selective norepinephrine and serotonin reuptake inhibitory effects and has similar potencies for the both transporters . The nature of the aromatic substituent R has a significant influence on the activity and selectivity of the compounds as inhibitors of the serotonin or the norepinephrine transporters . See figure 5.
Cycloalkanol ethylamine scaffold
Venlafaxine contains a cycloalkanol ethylamine scaffold. Increasing the electron-withdrawing nature of the aromatic ring provides more potent inhibitory effect of norepinephrine uptake and improves the selectivity for norepinephrine over the serotonin transporter . Effects of chloro, methoxy and trifluoromethyl substituents in the aromatic ring of cycloalkanol ethylamine scaffold were tested. The results showed that the strongest electron-withdrawing m-trifluoromethyl analogue exhibited the most potent inhibitory effect of norepinephrine and the most selectivity over serotonin uptake . See agents with cycloalkanol ethylamine scaffolds in figure 6.Milnacipran
Milnacipran is structurally different from other SNRIs . The SAR of milnacipran derivatives at transporter level is still largely unclear and is based on in vivo efficacy that was reported in 1987. N-methylation of milnacipran in substituent group R4 and R5 reduces the norepinephrine and serotonin activity . Researches on different secondary amides in substitution groups R6 and R7 showed that π electrons play an important role in the interaction between transporters and ligands. A phenyl group in substituent R6 showed effect on norepinephrine transporters. Substituent groups in R6 and R7 with allylic double bond showed significant improved effect on both norepinephrine and serotonin transporters . Studies have shown that when introducing a 2-methyl group in substituent R3 the potency at norepinephrine and serotonin transporters are almost abolished. Methyl group in substituent group R1 and R2 also abolished the potency at norepinephrine and serotonin transporters. Researchers found out that when replacing one of the ethyl groups of milnacipran with an allyl moiety increases the norepinephrine potency . The pharmacophorePharmacophore
thumb|right|300px|An example of a pharmacophore model.A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule....
of milnacipran derivatives is still largely unclear . The conformation of milnacipran is an important part of its pharmacophore. Changing the SAR in milnacipran changes the stereochemistry
Stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....
of the compound and affects the norepinephrine and serotonin concentration. Milnacipran is marketed as a racemic mixture. Effects of milnacipran resides in the 1S,2R-isomer and substitution of the phenyl group in the 1S,2R isomer has negative impact on norepinephrine concentration . Milnacipran has low molecular weight and low lipophilicity. Because of these properties milnacipran exhibits almost ideal 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...
in humans such as high 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...
, low inter-subject variability, limited liver enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
interaction, moderate tissue distribution and a reasonably long elimination half-life. Milnacipran´s lack of drug-drug interactions via cytochrome P450 enzymes is thought to be an attractive feature because many of the central nervous system drugs are highly lipophilic and are mainly eliminated by liver enzymes .
Future development of SAR
The application of an aryloxypropanamine scaffold has generated a number of potent MAOIs . Before the development of duloxetine, the exploration of aryloxypropanamine SAR resulted in the identification of fluoxetine and atomoxetine. The same motif can be found in reboxetine where it is constrained in a morpholineMorpholine
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...
ring system. Some studies have been made where the oxygen in reboxetine is replaced by sulfur
Sulfur
Sulfur or sulphur is the chemical element with atomic number 16. In the periodic table it is represented by the symbol S. It is an abundant, multivalent non-metal. Under normal conditions, sulfur atoms form cyclic octatomic molecules with chemical formula S8. Elemental sulfur is a bright yellow...
to give arylthiomethyl morpholine. Some of the arylthiomethyl morpholine derivatives maintain potent levels of serotonin and norepinephrine reuptake inhibition. Dual serotonin and norepinephrine reuptake inhibition resides in different enantiomers for arylthiomethyl morpholine scaffold . Possible drug candidates with dual serotonin and norepinephrine reuptake inhibitory activity have also been derived from piperazine, 3-amino-pyrrolidine and benzylamine templates .
Clinical trials
Several studies have shown that antidepressant drugs which have combined serotonergic and noradrenergic activity is more effective than SSRIs in treating MDD. Results showed that serotonergic-noradrenergic antidepressant drugs seem to have a modest efficacy advantage compared to SSRIs in treating MDD and have less side effects. Serotonergic-noradrenergic antidepressant drugs used to treat MDD compared to SSRIs and mirtazapineMirtazapine
Mirtazapine is a tetracyclic antidepressant used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications...
seem to be less expensive than other drugs for example in the UK. Further research is needed to examine whether larger differences between classes of antidepressant drugs might exist in specific MDD sub-populations or for specific MDD symptoms.
Data from clinical trials have indicated that SNRIs might have pain relieving properties. The pain perception and transmission in the central nervous system have not been fully elucidated however, extensive data support a role of serotonin and norepinephrine in the modulation of pain. This is also supported by data from clinical trials in humans in which antidepressants have been shown to reduce pain and functional impairment in central and neuropathic pain conditions. This property of SNRIs might be used to reduce doses of other pain relieving medication and lower frequency of limited efficacy, safety and tolerability issues.
Clinical research data have shown in patients with GAD that the SNRI duloxetine is significantly more effective than placebo in reducing painful physical symptoms of GAD after short-term and long-term treatment. Findings suggested that painful physical symptoms reoccur with relapsing that indicate a need for ongoing treatment in patients with GAD and concurrent painful physical symptoms.
Current status
LevomilnacipranLevomilnacipran
Levomilnacipran is an antidepressant currently under development by Forest Laboratories for the treatment of depression in the United States and Canada. As of 2009 it is in phase III clinical trials...
is the enantiomer of milnacipran. Like milnacipran, levomilnacipran is a selective SNRI. Levomilnacipran is currently under development for the treatment of MDD.
Bicifadine
Bicifadine
Bicifadine is a serotonin-norepinephrine reuptake inhibitor developed by DOV Pharmaceutical. It has been developed as an analgesic and is currently under development for the treatment of various pain conditions...
is a SNRI. Bicifadine is being developed for the treatment of acute
Acute
Acute may refer to:* Acute accent* Acute angle* Acute * Acute * Acute toxicity...
and chronic pain. Clinical research have shown that bicifadine is effective in the treatment of acute dental pain and bunionectomy pain. Bicifadine has also been reported to be as effective as the standard of care in reducing chronic lower back pain.
Products of SNRIs
| Active ingredient | Product name | Therapeutic use | Binding affinity (Ki nm) | Structure |
|---|---|---|---|---|
| Venlafaxine | Efexor® Effexor® | Treatment of treatment-resistant depression (TRD), generalized anxiety disorder (GAD), chronic pain syndromes | 5-HT:7,8 NE:1920 D:6050 |
|
| Milnacipran | Savella® Ixel® Dalcipran® Toledomin® | Treatment of pain and multiple symptoms associated with fibromyalgia syndrome, treatment of MDD | 5-HT:8,4 NE:22 D:>100000 |
|
| Duloxetine | Cymbalta® Ariclaim® Xeristar® Yentreve® | Treatment of MDD and fibromyalgia | 5-HT:0,07 NE:1,2 D:230 |
|
| Levomilnacipran | Not listed | Under development | 5-HT:NA NE:NA D:NA |
|
| Bicifadine | Not listed | Under development | 5-HT:NA NE:NA D:NA |
 |
| Desvenlafaxine | Pristiq® | Treatment of MDD in adults | 5-HT:NA NE:NA D:NA |
 |
| Sibutramine | Meridia® Reductil® | Treatment of obesity | 5-HT:NA NE:NA D:NA |
 |
5-HT: Serotonin - NE: Norepinephrine - D: Dopamine - NA: Not available
Abbreviations
- Serotonin–norepinephrine reuptake inhibitors (SNRI)
- Major depressive disorder (MDD)
- SerotoninSerotoninSerotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
(5-Hydroxytryptamine, 5-HT) - NorepinephrineNorepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
(NE, noradrenalin) - Serotonin transporterSerotonin transporterThe serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
(SERT) - Norepinephrine transporterNorepinephrine transporterThe norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....
(NET) - Selective serotonin reuptake inhibitors (SSRI)
- Norepinephrine reuptake inhibitorNorepinephrine reuptake inhibitorA norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
s (NRI) - Tricyclic antidepressants (TCA)
- Monoamine oxidase inhibitors (MAOI)
- Food and Drug AdministrationFood and Drug AdministrationThe 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) - Treatment-resistant depression (TRD)
- Generalized anxiety disorder (GAD)
- Structure activity relationship (SAR)
See also
- SerotoninSerotoninSerotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
(5-HT) - NorepinephrineNorepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
(NE) - Reuptake inhibitorReuptake inhibitorA reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
(RI) - Norepinephrine reuptake inhibitorNorepinephrine reuptake inhibitorA norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
(NRI) - Serotonin reuptake inhibitor (SRI)
- Selective serotonin reuptake inhibitorSelective serotonin reuptake inhibitorSelective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
(SSRI) - Serotonin–norepinephrine reuptake inhibitor (SNRI)
- Dopamine reuptake inhibitorDopamine reuptake inhibitorA dopamine reuptake inhibitor is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter...
(DRI) - Serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI)
- Norepinephrine-dopamine reuptake inhibitorNorepinephrine-dopamine reuptake inhibitorA norepinephrine-dopamine reuptake inhibitor is a drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter and the dopamine transporter , respectively...
(NDRI)