Sertraline structure

The 13C NMR chemical shift predictions for sertraline (Structure 1) are plotted in Figure 11. The correlation is quite high. The greatest deviations between observed and predicted chemical shifts are for the N-methyl carbon and for the two aromatic ring carbons to which chlorine atoms are attached. 

Tricyclic drugs have, as the name implies, a three-ring structure, and interfere with reuptake of norepinephrine and/or serotonin into axon terminals. Tricyclic drugs include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), and nortriptyline (Pamelor, Aventil). Tricyclics have the occasional but unfortunate cardiovascular side effects of arrhythmia and postural hypotension. Newer, nontricyclic antidepressants have been developed that are collectively referred to as SSRIs. These have a potent and selective action on serotonin, and lack the cardiovascular side effects of the tricyclics. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). A fifth SSRI, citalopram (Celexa) has been used in Europe and has recently been approved in the United States. Venlafaxine (Effexor) blocks reuptake of norepinephrine and serotonin, while bupropion (Wellbutrin) acts on both dopamine and norepinephrine. 

During the course of a study of the salts formed by saccharin with quinine, haloperidol, mirtazapine, pseudoephedrine, lamivudine, risperidone, sertraline, venlafaxine, zolpidem, and amlodipine, a 1 1 cocrystal of saccharin and piroxicam was detected [68]. In the crystal structure, the asymmetric unit was found to consist of one saccharin molecule and one zwitterionic piroxicam molecule that were linked by two sets of N—H O hydrogen bonds. The piroxicam-saccharin synthons were in turn linked through bridging C—H O hydrogen bonds. Interestingly, the drug substance solubility out of the cocrystal was found to be comparable to that of the marketed piroxicam product. 

The selective serotonin re-uptake inhibitors (SSRIs) that are currently available are fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, and escitalopram. They are widely marketed and are in many countries a major alternative to tricyclic antidepressants in the treatment of depression. The SSRIs are structurally diverse, but they are all inhibitors of serotonin uptake, with much less effect on noradrenaline. They have slight or no inhibitory effect on histaminergic, adrenergic, serotonergic, dopaminergic, and cholinergic receptors (1). 

Figure 8. Structures of the SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), the NSRI reboxetine, and the SNRI venlafaxine.

The diversity of the SSRIs is evident not only in their chemical structures, but also in their pharmacokinetic profiles. Fluoxetine has an elimination half-fife of 2 to 3 days (4 to 5 days with multiple dosing). The single-dose hah-hfe of norfluoxetine, the active metabolite, is 7 to 9 days. Paroxetine and sertrahne have half-lives of approximately 24 hours. Unlike paroxetine, sertraline has an active metabolite, but the metabohte contributes minimally to the pharmacologic effects. Escitalopram has a half-life of approximately 30 hours. Peak plasma concentrations of citalopram are observed within 2 to 4 hours after dosing, and the elimination half-life is about 30 hours. The SSRIs, with the exception of fluvoxamine, escitalopram, and citalopram, are extensively bound to plasma proteins (94% to 99%). The SSRIs are extensively distributed to the tissues, and aU, with the possible exception of citalopram, may have a nonlinear pattern of drug accumulation with long-term administration. ... 

Although sertraline appears to differ structurally from the other SSRIs, it is a phenylaminotetralin, in which the diphenylpropylamine nucleus is constrained into a rigid bicyclic ring system (Fig. 21.13). In the early work with the discovery of SSRIs at Pfizer, tametraline was initially synthesized in 1978. Animal studies showed it to be a stimulant and to block NE and DA uptake, a use that Pfizer was not interested in pursuing. Subsequently, one or two chlorine atoms were introduced into tametraline to produce new molecules that were potent inhibitors of 5-HT reuptake in the brain. One of the dichloro compounds was to become known as sertraline. 

Nomifensine is a substituted phenyipiperidine (an aminophenyitetrahydroisoquinoline) structurally related to sertraline that was marketed as a stimulatory antidepressant in the mid-1970s but later withdrawn because of a high incidence of hemolytic anemia. Nomifensine inhibits the NE and dopamine reuptake transporters. It displays high affinity for NET (human pK, = 7.8), moderate affinity for dopamine transporter (pK, = 6.6), and a low affinity for SERT (5-HT NE ratio, 65). 

The related agents paroxetine and sertraline (Fig. 11) contain two centers of chirality in their structures, but both are marketed as single stereoisomers. The latter agent is interesting because the stereochemistry of the molecule has a marked influence on the selectivity of drug action (Table 2). In the case of the irons isomers, the (- -)-enantiomer is a potent inhibitor of the uptake of serotonin, dopamine, and noradrenaline, the (—)-enantiomer being relatively selective for inhibition of noradrenaline uptake. In contrast, with the cis isomers, a separation of activity occurs with the (- -)-15,45-stereoisomer, sertraline, retaining potent serotonin uptake inhibition activity [87,88]. The selectivity of action, expressed as a concentration ratio for the inhibition of dopamine and noradrenaline... 

The structure of sertraline is characterized by two stereogenic centres with absolute (15,45) configuration and relative c -configuration. The compound can be obtained from an enantiomerically pure natural chiral compound, as presented in Sect. 7.7. However, a more effective approach was initiated from achiral materials by transforming them diastereoselectively, followed by chiral separations of the enantiomers [11]. 

The use of chiral columns of various types has exploded since the 1980s, as the need for laboratory-scale and preparative-scale separation of enantiomers has increased. A number of chiral drugs are prepared for commercial purposes using chiral chromatography, for example, the antidepressant Zoloft (chemical name S-sertraline) [26]. Its absolute structure is shown in Figure 5.19 [27]. 

Figure 5.15. Molecular structure of methamphetamine Figure 5.16. Molecular structure of phenylephrine Figure 5.17. Molecular structure of paclitaxel Figure 5.18. Molecular structure of S-citalopram Figure 5.19. Molecular structure of S-sertraline...

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