Science and Technology Production
Article
Authorship
Berenguer, Inmaculada
;
Aouad, Noureddine El
;
ANDUJAR, SEBASTIAN ANTONIO
;
Romero, Silvia Vanessa
;
Suvire, Fernando Daniel
;
Freret, Thomas
;
Bermejo, Almudena
;
Ivorra, María Dolores
;
ENRIZ, RICARDO DANIEL
;
Boulouard, Michel
;
Cabedo, Nuria
;
Cortes, Diego
Date
2009
Publishing House and Editing Place
PERGAMON-ELSEVIER SCIENCE LTD
Magazine
BIOORGANIC & MEDICINAL CHEMISTRY.,
vol. 17
(pp. 4968-4980)
PERGAMON-ELSEVIER SCIENCE LTD
Summary
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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 affi...
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.
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Key Words
TETRAHYDROISOQUINOLINESSTRUCTURE-ACTIVITY RELATIONSHIPSIN VIVO BEHAVIORAL ASSAYSDOPAMINE RECEPTORSTHEORETICAL CALCULATIONS
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