Selective 5-HT reuptake inhibitors

Several other clinically available pharmacological agents have been tested for their potential to facilitate smoking cessation, although they are not approved by the FDA for this purpose. For example, tricyclic antidepressants, which inhibit reuptake of noradrenaline and 5-HT, promote smoking cessation in conjunction with behavioral treatment in some individuals.107 However, these medications are limited because of their significant side effects. 5-HT-selective reuptake inhibitors (SSRIs) are believed to be a safer class of antidepressants but have not demonstrated effectiveness in smoking cessation.108... 

Several of the 5-HT selective reuptake inhibitors are in clinical use today. 

Duloxetine (LY-248686), (S)-(-i-)-N-methyl-3-(l-naphthyloxy)-3-(2-thienyl)propyl-amine, is expected to be not only a new potent antidepressant but also a NE (norepinephrine) reuptake inhibitor, a 5-HT (serotonin) reuptake inhibitor, and a new treatment drug for stress urinary incontinence [18]. In order to produce an enantiopure key intermediate for the synthesis of the (S)-amine, the Eli Lilly group proposed various strategies [19]. As a result, they selected the enantioseparation of racemic 3-(dimethylamino)-l-(2-thienyl)propan-l-ol with (S)-mandelic acid by diastereomeric salt formation as the most economic and suitable process for industrial-scale production with efficient supporting techniques such as the racemization of the antipode and recycling the recovered materials [20]. However, in the process of demethylation for the preparation of (S)-Duloxetine from (S)-3-(di-methylamino)-l-(2-fhienyl)propan-l-ol, there are some critical problems, such as low yield and considerable decomposition to give impurities. Thus, a direct synthesis of (S)-Duloxetine starting from (S)-3-(methylamino)-l-(2-thienyl)propan-l-ol is expected to be a new route for the production of (S)-Duloxetine. 

The only structural difference between these two examples (Fig. 18.19) is represented by the heteroatom which makes them classical bioisosteres since both oxygen and sulphur have the same valence. Both may be classified as mixed 5-HT/NA reuptake inhibitors but replacement of the oxygen atom with sulphur appears to shift the selectivity from NAT to SERT. 

Until the introduction of selective serotonin reuptake inhibitors (SSRIs) in the 1980s, tricyclic antidepressants were the most widely used drugs. The therapeutic effect of amitriptyline and imipramine are related to their ability to inhibit the presynaptic reuptake of both NA and 5-HT. They are referred to as non-selective reuptake inhibitors, whereas many of the other tricyclics are more selective thus, clomipramine is a selective reuptake inhibitor for 5-HT and desipramine and nortriptyline are selective... 

The older tricyclic agents show less than a ten-fold selectivity in inhibiting noradrenaline over that for 5-HT (e.g. desipramine, imipramine, nortriptyline) through amitryptyline. which shows virtually no selectivity, to trazodone, zimelidine and clomipramine, which are somewhat 5-HT selective. The newer Serotonin-Selective Reuptake Inhibitors (SSRIs) show a higher selectivity for inhibition of 5-HT reuptake in the brain, and have a different pharmacology. Examples clinically used include citalopram, fluoxetine, fluvoxamine, nefazodone, paroxetine, sertraline, trazodone and venlafaxine. Experimental agents include 6-nitroquipazine, alaproclate, litoxetine, indatraline and p-CIT. 

A mechanism for altering synaptic availability of 5-HT is inhibition of presynaptic reaccumulation of neuronally released 5-HT. Selective serotonin reuptake inhibitors (SSRIs e.g., fluoxetine [PROZAC]) potentiate and prolong the action of 5-HT released by neuronal activity. Effects of 5-HT-active drugs, like the SSRIs, in anxiety and depressive disorders strongly suggest an effect of 5-HT in the neurochemical mediation of these disorders. SSRIs are the most widely used treatment for endogenous depression (see Chapter 17). 

Fluoxetine is a potent and selective inhibitor of 5-HT reuptake, but not of NE or dopamine uptake in the CNS. Its mechanism of action is common to the SSRIs. Fluoxetine does not interact directly with postsynaptic 5-HT receptors and has weak affinity for the other neuroreceptors. Both enantiomers of fluoxetine display similar affinities for human SERT. The NE 5-HT selectivity ratio, however, indicates that the S-enantiomer is approximately 100 times more selective for SERT inhibition than the R-enantiomer. The R-(+)-stereoisomer is approximately eight times more potent an inhibitor of SERT together with a longer duration of action than the S-(-)-isomer. However, the S-(-)-norfluoxetine metabolite is seven times more potent as an inhibitor of the 5-HT transporter than the R-(+)-metabolite, with a selectivity ratio approximately equivalent to that of S-fluoxetine (55,56). 

Beginning in the 1960s, ben2odia2epiae anxiolytics and hypnotics rapidly became the standard prescription dmg treatment. In the 1980s, buspkone [36505-84-7] (3), which acts as a partial agonist at the serotonin [50-67-9] (5-hydroxytryptamine, 5-HT) type lA receptor, was approved as treatment for generali2ed anxiety. More recently, selective serotonin reuptake inhibitors (SSRIs) have been approved for therapy of panic disorder and obsessive—compulsive behavior. 

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Indeed, 5-HT is also a substrate for the 5-HT transporter, itself an important player in the treatment of depression, and more recently for the whole range of anxiety disorders spectrum (GAD, OCD, social and other phobias, panic and post-traumatic stress disorders). It is the target for SSRIs (selective serotonin reuptake inhibitors) such as fluoxetine, paroxetine, fluvoxamine, and citalopram or the more recent dual reuptake inhibitors (for 5-HT and noradrenaline, also known as SNRIs) such as venlafaxine. Currently, there are efforts to develop triple uptake inhibitors (5-HT, NE, and DA). Further combinations are possible, e.g. SB-649915, a combined 5-HTia, 5-HT1b, 5-HT1d inhibitor/selective serotonin reuptake inhibitor (SSRI), is investigated for the treatment of major depressive disorder. 

Sharp, T, Umbers, V and Gartside, SE (1997) Effect of a selective 5-HT reuptake inhibitor in combination with 5-HTlA and 5-HTlB receptor antagonists on extracellular 5-HT in rat frontal cortex in vivo. Br. J. Pharmacol. 121 941-946. 

Recent evidence indicates that the 5-HT transporter is subject to post-translational regulatory changes in much the same way as neurotransmitter receptors (Blakeley et al. 1998). Protein kinase A and protein kinase C (PKC), at least, are known to be involved in this process. Phosphorylation of the transporter by PKC reduces the Fmax for 5-HT uptake and leads to sequestration of the transporter into the cell, suggesting that this enzyme has a key role in its intracellular trafficking. Since this phosphorylation is reduced when substrates that are themselves transported across the membrane bind to the transporter (e.g. 5-HT and fi -amphetamine), it seems that the transport of 5-HT is itself linked with the phosphorylation process. Possibly, this process serves as a homeostatic mechanism which ensures that the supply of functional transporters matches the demand for transmitter uptake. By contrast, ligands that are not transported (e.g. cocaine and the selective serotonin reuptake inhibitors (SSRIs)) prevent the inhibition of phosphorylation by transported ligands. Thus, such inhibitors would reduce 5-HT uptake both by their direct inhibition of the transporter and by disinhibition of its phosphorylation (Ramamoorthy and Blakely 1999). 

All TCAs are either secondary- or tertiary-amines of a dibenzazepine nucleus (Fig. 20.3), and they all inhibit neuronal reuptake of noradrenaline and/or 5-HT but are much less potent as dopamine reuptake blockers. A common claim is that secondary amines (e.g. desipramine) are preferential inhibitors of noradrenaline uptake whereas the tertiary derivatives (e.g. imipramine, doxepin and amitryptyline) preferentially inhibit 5-HT uptake. However, when Richelson and Pfenning (1984) actually compared the effects of a wide range of antidepressants on the synaptosomal uptake of [ H]monoamines in vitro, and compared their A s, instead of merely ranking /C50S collected from different studies, they found that tertiary- and secondary-substituted compounds were equi-potent inhibitors of [ H]noradrenaline uptake. Moreover, all the TCAs turned out to be more potent inhibitors of [ H]noradrenaline than of [ H]5-HT uptake. Tertiary amines are even less convincing inhibitors of 5-HT reuptake in vivo, because any such action is diminished by their metabolism to secondary amines (e.g. imipramine to desipramine amitriptyline to nortriptyline). Only clomipramine retains any appreciable 5-HT uptake blocking activity in vivo with (an unimpressive) five-fold selectivity for 5-HT versus noradrenaline. 

Paroxetine is the most potent inhibitor of 5-HT reuptake but, in terms of distinguishing one compound from another, their preferential selectivity for inhibition of 5-HT rather than noradrenaline reuptake is the key criterion. Citalopram is by far the most selective in vitro (1500-3000-fold) and fluoxetine, the most frequently prescribed SSRI in the UK, is the least selective of all these agents (see Stanford 1999). In fact, it is worth questioning whether fluoxetine is a true SSRI at all. 

The combination of antidepressants is a common clinical practice. The most usual pharmacological profile is serotoninergic-noradrenergic (96%) and the most popular combinations are selective 5-HT reuptake inhibitor (SSRI) + mir-tazapine, SSRI + reboxetine, and SSRI + TCAs (De la Gandara et al. 2005). 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

MAOI non-selective monoamine oxidase (A/B) inhibitors RIMA reversible inhibitor of monamine oxidase type A SSRI selective serotonin (5-HT) reuptake inhibitors SNRI serotonin/noradrenaline reuptake inhibitor SNARI selective noradrenaline (NA) reuptake inhibitor NA = 5-HT — DA potency of the drug is very similar in raising the level of both (or all three) monamines NA > 5-HT more selective for NA 5-HT>NA more selective for 5-HT NA increases the release of NA. 

It has been known for over 25 years that many of the tricyclic antidepressants (TCAs), e.g. imipramine and amitriptyline, are potent inhibitors of both norepinephrine and 5-HT reuptake. Some tricyclic antidepressants, e.g. desipramine, inhibit the uptake of norepinephrine much more potently than the uptake of 5-HT. Thus, it was unclear for some time whether the inhibition of 5-HT uptake played any role in the antidepressant action of those TCAs that possessed this pharmacological property. Recently, however, effective antidepressants such as fluoxetine, paroxetine and sertraline have been marketed and these SSRIs are much more potent inhibitors of the uptake of 5-HT than that of norepinephrine (Fig. 13-8). Thus, selective inhibition of the uptake of either norepinephrine or 5-HT can result in an antidepressant effect (Ch. 55). 

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