Sertraline derivatives

Differences exist in primary care between the patterns of prescribing fluoxetine, paroxetine or sertraline, which may influence cost outcomes. Sertraline-treated patients are more likely to have their dose increased (Sclar et al, 1995 Donoghue, 1998), and to drop out of treatment prematurely (Donoghue, 1998). The apparent need to titrate doses upwards with sertraline may require more involvement by the clinician and may delay response to treatment, with resultant increases in direct health costs (Sclar et al, 1995). However, these economic findings are retrospective, may suffer from selection bias, and being derived from HMO patients may not be generalizable to other populations confirmation in further studies is required. 

Because the SSRIs are derived from different chemical groups, their receptor interactions vary from compound to compound but, apart from paroxetine, none of them shows any appreciable binding to muscarinic receptors, a prime objective of their development. However, compared with other SSRIs, fluoxetine binds with moderately high affinity to human 5-HT2A (.K) 280 nM) and 5-HT2C receptors (Aij 55 nM) sertraline is a relatively potent ligand for ai-adrenoceptors, 2-adrenoceptors and Dj receptors and citalopram shows appreciable binding to 5-HTia, oc]-adrenoceptors and Hi receptors (Table 20.6 Stanford 1996). The extent to which any of these receptor interactions affects the efficacy of these compounds is not known. 

A series of DAT selective 3-phenyltropanes have been reported to have potential for treatment of cocaine abuse [33,36,37]. RTI-336,15 (reuptake IC50 — 4.1 nM) was the most potent among these tropane derivatives in locomotor activity and drug discrimination it was less stimulatory than cocaine, and had the slowest onset and longest duration of action. It also reduced self-administration of cocaine in rats and rhesus monkeys. Interestingly, in rhesus monkeys trained to self-administer cocaine, when coadministrated with either citalopram or sertraline, 15 produced significantly more robust reductions in cocaine self-administration compared with 15 alone [38]. 

Early studies from the Pfizer laboratories had revealed that compounds from a series of mzn.s-l-amino-4-phenyl-tetralins possessed potent norepinephrine (NE) uptake blocking activity. The activity was highly specific for the (1/ , 4S)-enantiomer and was confined to the trans derivatives. The corresponding (IS, 4/ )-enantiomer was much less active and the diastereomeric cis racemates were inactive at blocking NE uptake. It was subsequently shown that many compounds from the diastereomeric cis senes were unexpectedly potent and selective inhibitors of serotonin (5-HT) uptake, thus differentiating these compounds from the trans compounds. One of these compounds, sertraline (5), was originally discovered as a racemic mixture. Resolution showed that the (+)-enantiomer was several times more selective for 5-HT uptake blocking activity than the (-)-isomer. The (+)-enantiomer was subsequently shown to possess the in vivo behavioral effects expected of a potent and selective 5-HT blocker. Thus, as opposed to... 

Pharmacokinetic data is derived from ingestion of doses considered to be in the therapeutic range hence, no data are included on the pharmacokinetics of sertraline after overdose. 

In this process (Fig. 22), ketone 61 underwent reduction with an over-stoichiometric amount of borane in THF in the presence of 5 mol % of the proline-derived Corey s oxa-zaborolidine 62 to afford alcohol 63 in 100% yield and 92% e.e. SN2 displacement carried out on the alcohol mesylate with a higher-order cuprate gave adduct 64, that was transformed first into tetralone 65 by a triflic acid-promoted Friedel-Crafts-type reaction, and then into sertraline 66 (86% e.e.) by imine formation and borohydride reduction. 

Sertraline The proposed method is based on reaction of sertraline with chloranihc acid. First derivative spectrophotometry has been evaluated by measuring the derivative signal at 475.72 nm -588.40 nm (peak to peak amplitude). Calibration graph was established for 5-100 pg mL-i of sertraline 13... 

Biological target Sertraline is an aryl-substituted tetrahydronaphthalene derivative which selectively inhibits the plasma membrane serotonin transporter (SERT) and thereby blocks serotonin re-uptake from the neuronal synapse. 

Krumlinde, P., Bogar, K., and Backvall, J. E. (2010). Asymmetric synthesis of bicyclic diol derivatives through metal and enzyme catalysis Application to the formal synthesis of sertraline. Chem. Eur.., 16,4031-4036. 

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