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 Discovery and development of dual serotonin and norepinephrine reuptake inhibitors 

Introduction
Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant drugs used in the treatment of major depressive disorder (MDD) and is a potent inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE, noradrenalin) reuptake, which are neurotransmitters in the brain that are known to play an important part in mood. The human serotonin transporter (SERT) and norepinephrine transporter (NET) are membrane proteins that are responsible for the re-uptake of serotonin and norepinephrine, respectively. Transport of serotonin and norepinephrine is sensitive to nanomolar concentrations of dual SERT/NET reuptake inhibitors including serotonin-norepinephrine reuptake inhibitors (SNRIs). Balanced dual inhibition of monoamine reuptake processes possibly may offer advantages over other antidepressants drugs by treating a wider range of symptoms Cashman, J. R. and Ghirmai, S. (2009). Inhibition of serotonin and norepinephrine reuptake and inhibition of phosphodiesterase by multi-target inhibitors as potential agents for depression. Bioorganic & Medicinal Chemistry, 17, 6890–6897. SNRIs are second-generation agents, such as the selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs). Over the past 2 decades, second-generation agents have gradually replaced first-generation agents, such as the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) as the drugs of choice for the treatment of MDD, mainly because of their improved tolerability and safety profile if taken in overdose.

History
Since the late 1980s selective serotonin reuptake inhibitors (SSRIs) have dominated the antidepressant market but now there is increased interest in antidepressants with broader mechanisms of action that may offer improvements in efficacy and adverse events. In 1993 the drug company Wyeth (now part of Pfizer) introduced to the US market a new SNRI called venlafaxine (Effexor®)ref>Gutierrez, M. A., Stimmel, G. L. and Aiso, J. Y. (2003). Venlafaxine: A 2003 Update. Clinical Therapeutics, 25(8), 2138-2154. Venlafaxine (l-[2-dimethylaminol-1-[(4-methoxyphenyl) ethyll cyclohexanol) was the first compound ever described of a new class of antidepressive substances: the phenylethylamines. These substances are unrelated to tricyclic antidepressants and other selective serotonin reuptake inhibitors. Venlafaxine blocks the neuronal reuptake of serotonin, noradrenaline, and, to a lesser extent, dopamine in the central nervous system. Venlafaxine has no inhibitor activity over monoamine oxidase and shows slight or no affinity for muscarinic, cholinergic, histaminergic-, or alpha-adrenergic receptors. In contrast with several other antidepressant drugs, venlafaxine can induce a rapid onset of action, mainly due to a subsequent norepinephrine reuptake inhibition. Venlafaxine has become the first and most commonly used drug in the search for antidepressants that may be more effective than SSRIs in achieving remission of symptoms of major depression. It is also effective for treatment-resistant depression (TRD). Finally, the extended-release formulation is an established effective treatment option for generalized anxiety disorder (GAD) and is increasingly used for other anxiety disorders as well as some chronic pain syndromes.

In August 2004 the United States Food and Drug Administration (FDA) initially approved a new compound by Eli Lilly and Company called duloxetine (Cymbalta®), a dual reuptake inhibitor of serotonin and norepinephrine. Duloxetine ((+)/(S)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine) is used for the treatment of MDD. In September 2004 FDA approved duloxetine treatment for diabetic peripheral neuropathic pain (DPNP). Duloxetine is the first drug that FDA approves for treatment for DPNP, where the goal of treatment is the management of pain symptoms associated with diabetic peripheral neuropathy (DPN). In Februrary 2007 duloxetine was also approved for the treatment of for generalized anxiety disorder.

In February 2008 FDA approved a new drug from Wyeth called desvenlafaxine (Pristiq®) for the treatment of adult patients with MDD and is the third SNRI approved by the FDA for the treatment of MDD. Desvenlafaxine is also being investigated for the treatment of vasomotor symptoms (VMS) associated with menopause, and clinical trials are under way investigating the possible use of desvenlafaxine for the treatment of fibromyalgia and neuropathic pain.

Overview of SNRI
Venlafaxine (Efexor®, Effexor®) was the first drug described in the class of serotonin-norepinephrine reuptake inhibitors. Venlafaxine inhibits reuptake of serotonin and norepinephrine .Venlafaxine was approved by the Food and Drug Administration in the US in 1993 for the treatment of treatment-resistant depression. Venlafaxine with extended-release was also introduced to the US market for the treatment of generalized anxiety disorder as well as chronic pain syndromes.

Desvenlafaxine (Pristiq®) is the active metabolite of venlafaxine. Desvenlafaxine is a serotonin-norepinephrine reuptake inhibitor like venlafaxine and is used in treatment of major depressive disorder in adults. Desvenlafaxine was approved by the US Food and Drug Administration in 2008 and was then the third approved serotonin-norepinephrine reuptake inhibitor.

Duloxetine (Cymbalta®, Ariclaim®, Xeristar®, Yentreve®) was the second serotonin-norepinephrine reuptake inhibitor approved by the US Food and Drug Administration in 2004. Duloxetine is used in treatment of major depressive disorder and fibromyalgia. Milnacipran (Savella® Ixel®, Dalcipran®, Toledomin®) is an serotonin-norepinephrine reuptake inhibitor. Milnacipran was approved by the US Food and Drug Administration in 2009 for the treatment of pain and multiple symptoms associated with fibromyalgia syndrome. Milnacipran is also used in the treatment of major depressive disorder.

Sibutramine (Meridia®, Reductil®) is a serotonin-norepinephrine reuptake inhibitor used in the treatment of obesity. Sibutramine was first approved by the US Food and Drug Administration in 1998 and was then a new class of medication for the treatment of obesity to be approved in 30 years.

Drug discovery and design
Fluoxetine (1) (Fig. 1) is að widely used selective serotonin reuptake inhibitor (SSRI) for depression and other neuropshychiatric disorders. Norepinephrine reuptake inhibitors (NRI) are fewer in clinical use. Atomoxetine (2) in a norepinephrine reuptake inhibitor which is used in the treatment of attention deficit hyperactivity disorder or ADHD. Another example of a norepinephrine reuptake inhibitor is Reboxetine (3) which is used for major depressive disorder og MDD. Dual acting serotonin and norepinephrine reuptake inhibitors (SNRI) are a younger class og drug that has an improved efficiacy and/or faster onset of action compared to selective serotonin reuptake inhibitors. An example of two drugs in this class are Venlafaxine (4) and Duloxetine (5) and are used as an antidepressant drug. Duloxetine has also been used to treat pain stress urinary incontinence. Research continues on development of pharmaceutical agnets that posess these properties. These chemicals all share a common aryloxypropanamine scaffold (Fig. 2). Monoamine reuptake inhibitors contain a aryloxypropanamine moiety. Selectivity depends upon the substitution pattern of the aryloxy ring. Selective norepinephrine reuptake inhibitors contain a substitution in 2‘- position of the aryloxy ring but selective serotonin reuptake inhibitors contain a substitution in 4‘- position of the aryloxy ring. Dual acting serotonin and norepinephrine reuptake inhibitors contain two phenyl groups in 2‘ and 3‘- position af the aryloxy ring and has similar potencies for the two transporters.

Mechanism of action
Monoamines are connected to the pathophysiology of depression. Symptoms are thought to appear because concentrations of neurotransmitters like norepinephrine and serotonin are insufficient. Medications for depression symptoms are established mostly on the pharmacology. These medications mechanisms of action effects the transmission of serotonin, norepinephrine and/or dopamine. For example, very simplified mechanisms of action for older, more unselective antidepressants, like tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAO), is that these medications act by inhibiting the reuptake, or metabolism, of norepinephrine and/or serotonin in the brain, which concludes higher neurotransmitters concentrations. Antidepressants that are believed to have dual mechanisms of action, inhibits both serotonin and norepinephrine reuptake, in some cases with weak effects on dopamine reuptake. Consequences of many antidepressants are 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 cunduction and cardiactoxicity. Selectivity of antidepressant agents are based on the neurotransmitters that are thought to have influence on depression symptoms. Drugs that selectively block the reuptake of serotonin and/or norepinephrine, are successful for treating depression, and are much 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
The first medications that had dual mechanism of action were the TCAs. The mechanism of action for the tricyclic secondary amine antidepressants is only partly understood, and is rather complex. TCAs have dual inhibition effects on the norepinephrine reuptake transporters and serotonin reuptake transporters. Increased norepinephrine and 5-HT concentrations are obtained by inhibiting both of these transporter proteins. The TCAs have substantially more affinity for the norepinephrine reuptake protein than the selective serotonin reuptake inhibitors (SSRIs), because of formation of secondary amine TCA metabolites. . In addition, the TCAs interact with adrenergic receptors. This interaction seems to be critical for reaction to increased availability of norepinephrine in or near the synaptic clefts. 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. That mechanism is through 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 which result in smooth muscle relaxation or decreased secration. Likely explanation for effects on neurotransmitter release is as the receptors activates, inhibition of neurotransmitter release occurs, including suppression of voltage-gated Ca2+ currents and activation of G protein-coupled receptor-operated K+ currents. Attendance of Ca2+ causes depolarization and therefore norepinephrine release. Norepinephrine interacts with postsynaptic α- and β-adrenergic receptor subtypes and presynaptic α2-autoreceptors. TCAs activate negative-feedback mechanism, through its effects on presynaptic receptor mediation. Thus, repeated administration of ligands with that mechanism, results in decreased responses of α2-receptors, which leads to inhibition of neurotransmitter release, as mentioned above. Overall, inhibition of norepinephrine reuptake induced by TCAs, leads to decreased rates of neuron firing (mediated through α2-autoreceptors), metabolic activity, and release of neurotransmitter Because of multiple effects on different receptors, there are though many unwanted additional effects of TCAs, like poor tolerability (many adverse effects) and risk of toxicity

Selective serotonin reuptake inhibitors
Medications in this widely used group of antidepressants, called selective serotonin reuptake inhibitors (SSRIs), all selectively inhibits the reuptake of serotonin. With increased receptors selectivity, undesired effects like poor tolerability, are avoided. Serotonin is synthesized from L-tryptophan, an amino acid which is found in several food products. Active transport 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, influences the symptoms of anxiety coexistent 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 norepinephrine reuptake inhibitors, neuronal activity in locus coeruleus region is induced because of increased concentration of norepinephrine in the synaptic cleft, which results in activation of α2-adrenoreceptors, as discussed in section 3.1.1. Assays have shown that selective norepinephrine reuptake inhibitors have insignificant penchant for muscarinic-cholinergic, α1- and α2-adrenergic or H1-histaminergic receptors.

Dual serotonin and norepinephrine reuptake inhibitors
Combination of several mechanisms of action in a single active agent is an essential development in psychopharmacology. By combinate reuptake inhibition of serotonin and norepinephrine, improved potency and onset action acceleration are achieved, with improved antidepressants activity.

Clinical trials
Several studies have shown that antidepressant drugs which have combined serotonergic and noradrenergic activity is brandon was the creater of footballSRIs in treating major depressive disorder and have less side effects .Serotonergic-noradrenergic antidepressant drugs used to treat major depressive disorder compared to SSRIs and mirtazapine 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 major depressive disorder sub-populations or for specific major depressive disorder symptoms.

Data from clinical trials have indicated that serotonin-norepinephrine reuptake inhibitors 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 for the monoamine neurotransmitters, 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 serotonin-norepinephrine reuptake inhibitors 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 generalized anxiety disorder that the serotonin-norepinephrine reuptake inhibitor duloxetine is significantly more effective than placebo in reducing painful physical symptoms of generalized anxiety disorder 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 generalized anxiety disorder and concurrent painful physical symptoms. Milnacipram and Duloxetine are both approved by the US Food and Drug administration for the treatment of fibromyalgia.

Current status
Levomilnacipran is the enantiomer of milnacipran. Like milnacipran, levomilnacipran is a selective norepinephrine-serotonin reuptake inhibitor. Levomilnacipran is currently under development for the treatment of major depressive disorder.

Bicifadine is a norepinephrine-serotonin reuptake inhibitor. Bicifadine is being developed for the treatment of acute and chonic 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.