Selective serotonin reuptake inhibitors enantiomers

The selective serotonin reuptake inhibitors (SSRIs) represent a chemically diverse class of agents that have as their primary action the inhibition of the serotonin transporter (SERT) (Figure 30-3). Fluoxetine was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice. The development of fluoxetine emerged out of the search for chemicals that had high affinity for monoamine receptors but lacked the affinity for histamine, acetylcholine, and adrenoceptors that is seen with the tricyclic antidepressants (TCAs). There are currently six available SSRIs, and they are the most common antidepressants in clinical use. In addition to their use in major depression, SSRIs have indications in GAD, PTSD, OCD, panic disorder, PMDD, and bulimia. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Escitalopram is the S enantiomer of citalopram. As with all antidepressants,... 

Figure 11 Structures of the more active enantiomers of selective serotonin reuptake inhibitors (SSRI).

The stereoselective pharmacokinetics of the selective serotonin reuptake inhibitor, citalopram, have been studied in 10 healthy young subjects [139]. After administration of 40 mg racemate daily for 21 days by the oral route, stereoselectivity was found in citalopram plasma concentrations. The R(—) S(+) ratios of Cmax and AUCss were 1.5 and 1.6, respectively. No difference was noted in suggesting similar absorption rates of the enantiomers. The terminal phase values were 47 and 35 h for the R and S enantiomers, respectively. Renal clearance comprised 20% of each enantiomer s total clearance and was nonstereoselective. Although both enantiomers are extensively metabolized, both possess low hepatic extraction ratios [139]. Serotonin reuptake inhibition of citalopram primarily resides with the S enantiomer (see Chap. 5, Sec. 3.4 for more details), which attains lower concentrations in plasma. In eight geriatric patients (mean 77 y) given... 

Another example of chiral switching is that of the selective serotonin reuptake inhibitor (SSRI) antidepressant Celexa, which was introduced to the market in 1998 by Forest Laboratories. Celexa is a racemic mixture of (i )-citalopram oxalate and (5)-citalopram oxalate. While orrly the (S) enantiomer has therapeutic antidepressant properties, both enantiomers contribute to the side effects of the drug and therefore limit effectiveness and patient tolerance. In 2002, the FDA approved Lexapro, a new antidepressant derived from Celexa but from which the therapeutically ineffective (R) enantiomer has been removed. The benefits of isolating the active isomer include smaller required dosages, reduced side effects, and a faster and better patient response to the drag. 

Citalopram is a racemic bicyclic phthalane derivative and is a highly selective serotonin re-uptake inhibitor with minimal effects on noradrenaline and dopamine neuronal reuptake. Inhibition of 5-HT re-uptake by citalopram is primarily due to escitalopram, the active S-enantiomer of citalopram (1). One would expect escitalopram to be twice as potent as citalopram but otherwise not to differ significantly from the racemic mixture. However, escitalopram is marketed as being more efficacious than citalopram because, it is argued, the inactive R-isomer present in the racemate actually inhibits binding of the S-enantiomer to its site of action, the serotonin transporter. In some, but not all, clinical trials escitalopram has been statistically superior to citalopram in terms of speed of onset of therapeutic action and improvement on depression rating scales. The clinical significance of these differences is debatable (2). 

The antidepressant compound lubazodone (8) illustrates the breadth of the structural requirements for serotonin selective reuptake inhibitors the structure of this agent departs markedly from that of fluoxetine, the first drug in this class. The compound at hand also exemplifies the current trend for preparing drugs in chiral form. Thus reaction of the indanol (6) with the mesylate from chiral glycidic oxide in the presence of base leads to the epoxypropyl ether (7) with retention of chirality. Treatment intermediate 7 with aminoethylsulfonic acid closes the morpholine ring. Product 8 consists of pure (5) enantiomer. ... 

Asymmetric synthesis is also common. Another technique is kinetic resolution. Kinetic resolution relies upon a difference in reactivity between the two enantiomers. For example this technique can be used in the synthesis of duloxetine. Duloxetine is marketed as the hydrochloride salt under the tradename Cymbalta as an antidepressant. It is a selective serotonin and norepinephrine reuptake inhibitor. It is the S enantiomer which is used. 

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