Tetrahydroisoquinolines as dopaminergic ligands: 1-Butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline, a new compound with antidepressant-like activity in mice

Abstract

Three series of 1-substituted-7-chloro-6-hydroxy-tetrahydroisoquinolines (1-butyl-, 1-phenyl- and 1-benzyl derivatives) were prepared to explore the influence of each of these groups at the 1-position on the affinity for dopamine receptors. All the compounds displayed affinity for D1-like and/or D2-like dopamine receptors in striatal membranes, and were unable to inhibit [3H]-dopamine uptake in striatal synaptosomes. Different structure requirements have been observed for adequate D1 or D2 affinities. This paper details the synthesis, structural elucidation, dopaminergic binding assays, structure-activity relationships (SAR) of these three series of isoquinolines. Moreover, 1-butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline (1e) with the highest affinity towards D2-like receptors (Ki value of 66 nM) and the highest selectivity (49-fold D2 vs D1) by in vitro binding experiments was then evaluated in behavioral assays (spontaneous activity and forced swimming test) in mice. Compound 1e increased locomotor activity in a large dose range (0.04-25 mg/kg). Furthermore, this lead compound produced reduction in immobility time in the forced swimming test at a dose (0.01 mg/kg) that did not modify locomotor activity. The haloperidol (0.03 mg/kg), a D2 receptor preferred antagonist, blocked the antidepressant-like effect of compound 1e.