Inhibitors, monoamine reuptake

Non-selective monoamine reuptake inhibitors (NSMRI) are a group of antidepressants, which function by inhibiting the reuptake of noradrenaline... 

Jackson, HC, Needham, AM, Hutchins, LJ, Mazurkiewicz, SE and Heal, DJ (1997) Comparison of the effects of sibutramine and other monoamine reuptake inhibitors on food intake in the rat. Brit. J. Pharmacol. 121 1758-1762. 

Although many patients believe that dietary supplements will not interact with medications, recent literature suggests otherwise. Recently, many St. John s wort-drug interactions have been reported in the literature. Cases of patients developing symptoms of serotonin syndrome have been reported with St. John s wort alone and in concomitant therapy with other antidepressants such as monoamine oxidase inhibitors, serotonin reuptake inhibitors, and venlafaxine. St. John s wort may exacerbate the sedative effects of benzodiazepines, alcohol, narcotics, and other sedatives. St. John s wort may decrease the levels of protease inhibitors, cyclosporine, digoxin, and theophylline. 

Monoamine reuptake inhibitors elevate extracellular levels of serotonin (5-HT), norepinephrine (NE) and/or dopamine (DA) in the brain by binding to one or more of the transporters responsible for reuptake, namely the serotonin transporter (SERT), the norepinephrine transporter (NET) and the dopamine transporter (DAT), thereby blocking the reuptake of the neurotransmitter(s) from the synaptic cleft [1], Monoamine reuptake inhibitors are an established drug class that has proven utility for the treatment of a number of CNS disorders, especially major depressive disorder (MDD). 

Since the introduction of tricylic antidepressants (TCAs) almost 50 years ago, monoamine reuptake inhibitors with greatly improved safety profiles have significantly enhanced the treatment of depression [2,3]. Although TCAs are very effective antidepressants, cardiovascular, anticholinergic and sedative side effects... 

Considerable effort in the field of monoamine reuptake inhibitors is focused on improving antidepressant efficacy since 30-40% of patients do not respond to treatment with currently available agents [6,7], An additional major objective is to enhance the onset of action. Current antidepressants typically require 2-6 weeks of treatment before clinical efficacy is seen [6]. Clinical trials exploring augmentation strategies, in which a DA reuptake inhibitor or a dual NE/DA reuptake inhibitor is combined with an SSRI, have resulted in improved efficacy in depressed patients refractory to SSRI treatment alone [4,5]. The improved results from clinical trials such as these serve to justify the considerable focus on the development of inhibitors that simultaneously block the reuptake of 5-HT, NE and DA. 

Because of the continued need for better drugs to treat depression and the opportunities for new clinical indications, efforts to discover novel monoamine reuptake inhibitors continue unabated. This review will highlight developments in the discovery of novel agents that work via monoamine reuptake inhibition primarily based on publications that have appeared between 2005 and early 2007. New clinical indications for monoamine reuptake inhibitors will also be highlighted. A comprehensive review of publications on monoamine reuptake inhibitors between 2000 and July 2005 is available [3]. Approaches for the treatment of depression involving the augmentation of monoamine reuptake inhibitors with other CNS receptor modulators, and non-monoamine-based strategies have also been reviewed recently [6-8]. 

After more than a decade of use, bupropion (24) is considered a safe and effective antidepressant, suitable for use as first-line treatment. In addition, it is approved for smoking cessation and seasonal affective disorder. It is also prescribed off-label to treat the sexual dysfunction induced by SSRIs. Bupropion is often referred to as an atypical antidepressant and has much lower affinity for the monoamine transporters compared with other monoamine reuptake inhibitors. The mechanism of action of bupropion is still uncertain but may be related to inhibition of dopamine and norepinephrine reuptake transporters as a result of active metabolites [71,72]. In a recently reported clinical trial, bupropion extended release (XL) had a sexual tolerability profile significantly better than that of escitalopram with similar re-... 

Triple reuptake inhibitors (TRIs), which inhibit reuptake at all three transporters, have attracted considerable interest in recent years [77]. The involvement of dopamine reuptake in the etiology of depression and other CNS disorders has been recognized [29,30]. As a result, TRIs have been proposed to offer a faster onset of action and improved efficacy for depression over currently prescribed single or dual action monoamine reuptake inhibitors. Historically, the mesocorticolimbic dopamine pathway is thought to mediate the anhedonia and lack of motivation observed in depressed patients [78,79]. In addition, methylphenidate, both immediate release and extended release formula, has been found to be effective as an augmenting agent in treatment-resistant depression [4]. Furthermore, clinical studies using the combination of bupropion and an SSRI or SNRI have showed improved efficacy for the treatment of MDD in patients refractory to the treatment with SSRIs, SNRIs, or bupropion alone [5,80,81]. 

CHAPTER 2 Recent Developments in Monoamine Reuptake Inhibitors Shuang Liu and Bruce F. Molino 13... 

This conclusion is supported by the mechaiusm of action of imipramine. Once a neurotransmitter has been released into the synapse, there are two ways to terminate its action. The first is to degrade it to inactive products, by MAO for example. The second is to remove the neurotransmitter through reuptake into the presynaptic neuron. This mechaiusm is the predominant one for clearing the synapse of serotonin, norepinephrine, and dopamine. Specific proteins embedded in the neuronal plasma membrane mediate the reuptake of these monoamine neurotransmitters. Imipramine is a nonspecific monoamine reuptake inhibitor that is, it slows the reuptake of aU three of these monoamines, which enhances the activity of these neurotransmitters. This also suggests that a deficit in the activity of one or more of the monoamines underlies the problem of depression. 

Asymmetric allylic C-H activation of cydohexadiene systems has been used for the asymmetric synthesis of several compounds of pharmaceutical relevance. The key step in the asymmetric syntheses of the monoamine reuptake inhibitor (-i-)-indatrahne 185 was the C-H insertion reaction of the aryldiazoacetate 183 with 1,4-cyclohexadiene (Scheme 14.24). The product 184, obtained in 83% yield with 93% enantiomeric excess, is readily converted to (-i-)-indatraline using standard synthetic procedures [132]. 

Whitlock, G.A., Fish, P.V, Fray, M.J., Stobie, A. and Wakenhut, F. (2008) Pyridyl-phenyl ether monoamine reuptake inhibitors Impact of lipophilicity on dual SNRI pharmacology and off-target promiscuity. Bioorganic and Medicinal Chemistry Letters, 18, 2896—2899. 

Walter, M. M. (2005). Monoamine Reuptake Inhibitors Highlights of Recent Research Developments, Drug Development Research, 65 97-118. 

Atomoxetine (Straterra , originally tomoxetine or tomoxetin, 3) was first described and synthesized by chemists at Eli Lilly in the late 1970s and was one of the few compounds that was known to display meaningful selectivity for the norepinephrine reuptake transporter (NET) versus the serotonin reuptake transporter (SERT) and the dopamine reuptake transporter (DAT) (Barnett, 1986 Molloy and Schmiegel, 1997). Atomoxetine was one of several structurally related and commercially successful monoamine reuptake inhibitors that were developed by Lilly for the treatment of various psychiatric disorders (Eig. 17.4). Fluoxetine (43) and duloxetine (44) have both gained approval in the United States as Prozac and Cymbalta , respectively, and nisoxetine (45) is widely used as a tool in biology. 

Antidepressants as analgesics are almost a closed book as far as preclinical and clinical development is concerned. TCAs are an old drug class, and because of the rather problematic side-effect profile, interest in developing new drugs from this class is small. BL-1834 (Bioglan Lab.) is an intranasal formulation of doxepine that is in clinical development (phase II) for the treatment of severe pain. In patents on novel monoamine reuptake inhibitors, pain is usually claimed as a possible indication, but depression and anxiety are mentioned as the primary indications in most cases, and we are not aware of novel... 

Classical Antidepressants, Serotonin Selective and Noradrenergic Reuptake Inhibitors Monoamine Hypothesis of Antkfepresssant Action on Gene Expression... 

It has since been assumed that this is the therapeutic action of tricyclic antidepressants, which are sometimes referred to as monoamine reuptake inhibitors or MARIs. However the exact significance of this reuptake process is unknown, especially as the tricyclic antidepressants have numerous other actions and influence, directly or indirectly, almost all neurotransmitters, many neuropeptides and most hormones (Khan 1999). Further studies of reuptake by heart muscle preparations showed that chlorpromazine was a stronger reuptake inhibitor than imipramine and not all the tricyclic antidepressants had this action (Lahti Maickel 1971). In addition, it has not been possible to demonstrate that reuptake inhibition is actually correlated with increased availability or activity of noradrenalin or serotonin. In fact most evidence suggests that tricyclic drugs reduce levels of noradrenalin (Frazer Mendels 1977 Heydorn, Frazer, Mendels 1980 Schildkraut, Winokur, Applegate 1970). 

Atypical antidepressants represent a heterogeneous group comprising agents that interfere only weakly or not at all with monoamine reuptake (trazodone, nefazo-done, bupropion, mirtazapine), preferentially block reuptake of norepinephrine (re-boxetine), or act as dual inhibitors of 5-HT and norepinephrine reuptake (venlafaxine, milnacipran, duloxetine). Venlafaxine appears to be as effective as tricyclic antidepressants in severe depression. 

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