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

INMACULADA BERENGUER NOUREDDINE EL AOUAD , SEBASTIÁN ANDUJAR, VANESSA ROMERO, FERNANDO SUVIRE, THOMAS FRERET , ALMUDENA BERMEJO, MARÍA DOLORES IVORRA , RICARDO D. ENRIZ, MICHEL BOULOUARD, NURIA CABEDO, DIEGO CORTES.

BIOORGANIC & MEDICINAL CHEMISTRY.

Elsevier

Lugar: Amsterdam; Año: 2009 vol. 17 p. 4968 - 4980

0968-0896

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 onthe 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 immobilitytime in the forced swimming test at a dose (0.01 mg/kg) that did not modify locomotor activity. Thehaloperidol (0.03 mg/kg), a D2 receptor preferred antagonist, blocked the antidepressant-like effect of compound 1e.