Artículo
Tetrahydroisoquinolines as dopaminergic ligands: 1-Butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline, a new compound with antidepressant-like activity in mice
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
Fecha de publicación:
07/2009
Editorial:
Pergamon-Elsevier Science Ltd
Revista:
Bioorganic & Medicinal Chemistry
ISSN:
0968-0896
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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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Articulos(IMIBIO-SL)
Articulos de INST. MULTIDICIPLINARIO DE INV. BIO. DE SAN LUIS
Articulos de INST. MULTIDICIPLINARIO DE INV. BIO. DE SAN LUIS
Citación
Berenguer, Inmaculada; Aouad, Noureddine El; Andujar, Sebastian Antonio; Romero, Silvia Vanessa; Suvire, Fernando Daniel; et al.; Tetrahydroisoquinolines as dopaminergic ligands: 1-Butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline, a new compound with antidepressant-like activity in mice; Pergamon-Elsevier Science Ltd; Bioorganic & Medicinal Chemistry; 17; 14; 7-2009; 4968-4980
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