SL 81.0385: A novel selective and potent serotonin uptake inhibitor

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Abstract
SL 81.0385 (4‐[(2‐naphthalenyl)methoxy]piperidine) is a potent competitive inhibitor of serotonin uptake into rat hypothalamic synaptosomes and human platelets (IC50 values of 18 and 13 nM, respectively), which exhibits a high selectivity for inhibiting serotonin uptake relative to noradrenaline or dopamine uptake in vitro. SL 81.0385 also exhibits potent serotonin uptake inhibiting properties in vivo as demonstrated by its ability to antagonize the p‐chloroamphetamine‐induced depletion of rat cerebral serotonin levels (ED50 = 2.5 mg/kg i.p.). Similarly, SL 81.0385 is a potent inhibitor of 3H‐imipramine and 3H‐paroxetine binding to the serotonin transporter complex in rat cortical membranes (Ki values of 0.5 and 3.2 nM, respectively), but it exhibits a much lesser affinity for radioligand binding to the noradrenaline, adrenaline, and dopamine transporters. The selectivity of SL 81.0385 for serotonergic systems is also demonstrated by its effects on cerebral monoamine metabolism. Indeed, SL 81.0385 decreases, ex vivo, endogenous 5‐hydroxyindoleacetic acid (5‐HIAA) levels in the rat striatum, and, in vivo, extracellular 5‐HIAA concentrations (as measured by differential pulse voltammetry) in the rat cerebral cortex. In contrast, SL 81.0385 fails to decrease striatal levels of 3,4‐dihydroxyphenylacetic acid and homovanillic acid and hypothalamic levels of total, 3,4‐dihydroxyphenylethyleneglycol. SL 81.0385 is devoid of inhibitory activity toward monoamine oxidase and has no affinity for cerebral muscarinic, H1 histaminergic, α1‐, α2‐, and β‐adrenergic, D2 dopaminergic, and benzodiazepine receptors, and it possesses only weak affinity for 5‐HT2 receptors. The present results indicate that SL 81.0385 is a highly potent and selective inhibitor of serotonin uptake, chemically unrelated to the tricyclics, and it should find application in the treatment of depression, obesity, and alcoholism.