Tag: Selective serotonin reuptake inhibitor

Fluoxetine ((R/S)-N-methyl-3-phenyl-3-[(alpha,alpha,alpha-trifluoro-p-tolyl)oxy]propylamine; CAS 54910-89-3; molecular formula C17H18F3NO; molecular weight 309.33) is a phenoxyphenylpropylamine SSRI synthesized at Eli Lilly in 1972 and approved by the FDA in 1987 as the first commercial SSRI under the trade name Prozac. The compound exhibits high affinity for the serotonin transporter (SERT, Ki approximately 1 nM) with comparatively weak activity at the norepinephrine transporter (Ki approximately 240 nM) and the dopamine transporter. Notable for an extraordinarily long elimination half-life (1 to 3 days for the parent compound, 7 to 15 days for the active norfluoxetine metabolite) which renders steady-state achievement slow but mitigates discontinuation syndrome. Pharmacologically distinguished from later SSRIs by 5-HT2C antagonism that contributes to noradrenergic and dopaminergic disinhibition in the prefrontal cortex, partially explaining the activating subjective profile. Hepatic metabolism is via CYP2D6 (primary) and CYP3A4 (secondary); the compound is itself a potent CYP2D6 inhibitor, producing clinically significant interactions with TCAs, antipsychotics, and beta-blockers. Used widely as a reference SSRI in serotonergic mechanism studies, animal models of depression, and as a positive control in receptor binding and reuptake assays.

Sertraline ((1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine; CAS 79617-96-2; molecular formula C17H17Cl2N; molecular weight 306.23) is a tetrahydronaphthalene SSRI synthesized at Pfizer in 1977 and approved by the FDA in 1991 under the trade name Zoloft. SERT affinity is nanomolar (Ki approximately 0.3 nM); the compound exhibits weak dopamine transporter inhibition (Ki approximately 25 nM) that is unusual within the SSRI class and may contribute to a subtly different subjective profile. Plasma half-life is 22 to 36 hours; the principal metabolite N-desmethylsertraline is pharmacologically active but with reduced SERT affinity. Hepatic metabolism is via CYP2B6, CYP2C19, CYP2D6, and CYP3A4; clinically relevant CYP2D6 inhibition exists but is weaker than fluoxetine or paroxetine. Approved indications include major depressive disorder, OCD, panic disorder, PTSD, social anxiety disorder, and premenstrual dysphoric disorder. Used as a reference compound in SERT binding studies and animal models of depression and anxiety; the dichlorophenyl moiety is a target structural feature in numerous SSRI structure-activity relationship studies.

Paroxetine ((3S,4R)-3-[(2H-1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine; CAS 61869-08-7; molecular formula C19H20FNO3; molecular weight 329.36) is a phenylpiperidine SSRI developed at Ferrosan and licensed to SmithKline Beecham (now GSK), approved by the FDA in 1992 under the trade name Paxil. SERT affinity is the highest of any SSRI (Ki approximately 0.13 nM); off-target activity at muscarinic acetylcholine receptors (Ki approximately 100 nM) produces sedation and dry mouth at clinical doses, and weak NET inhibition contributes to noradrenergic effects at higher doses. Plasma half-life is approximately 21 hours with significant interpatient variability driven by CYP2D6 polymorphism (paroxetine is both a substrate and a potent inhibitor of CYP2D6, producing nonlinear pharmacokinetics at high doses). The compound exhibits the most pronounced discontinuation syndrome of the SSRI class, attributed to the relatively short half-life and muscarinic rebound on cessation. Used as a high-affinity SERT reference compound in receptor binding assays and as a comparator in OCD and anxiety disorder research.

Citalopram (1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile; CAS 59729-33-8; molecular formula C20H21FN2O; molecular weight 324.39) is a bicyclic phthalane SSRI developed at H. Lundbeck in Denmark and approved in Europe in 1989 and by the FDA in 1998 under the trade name Celexa. The compound is sold as the racemate; the (S)-enantiomer (escitalopram) accounts for essentially all SERT inhibitory activity, while the (R)-enantiomer is largely inactive but may attenuate the (S)-enantiomer’s binding through allosteric SERT interaction. SERT affinity ((S)-enantiomer): Ki approximately 1 nM; selectivity over NET and DAT exceeds 1000-fold, making citalopram the most selective SSRI in clinical use. Plasma half-life is 33 to 37 hours; hepatic metabolism via CYP2C19, CYP3A4, and CYP2D6 produces minimally active metabolites. The compound is associated with dose-dependent QTc prolongation (FDA boxed warning issued 2011), with the maximum recommended dose reduced from 60 mg to 40 mg as a result. Used as the canonical selective SERT inhibitor in mechanism studies and as a reference compound in SSRI structure-activity work.