Tetrahydroisoquinolines as dopaminergic ligands: 1-Butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline, a new compound with antidepressant-like activity in mice. - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Bioorganic and Medicinal Chemistry Année : 2009

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

Inmaculada Berenguer
  • Fonction : Auteur
Noureddine El Aouad
  • Fonction : Auteur
Sebastián Andujar
  • Fonction : Auteur
Vanessa Romero
  • Fonction : Auteur
Fernando Suvire
  • Fonction : Auteur
Almudena Bermejo
  • Fonction : Auteur
María Dolores Ivorra
  • Fonction : Auteur
Ricardo D Enriz
  • Fonction : Auteur
Nuria Cabedo
  • Fonction : Auteur
Diego Cortes
  • Fonction : Auteur

Résumé

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 D(1)-like and/or D(2)-like dopamine receptors in striatal membranes, and were unable to inhibit [(3)H]-dopamine uptake in striatal synaptosomes. Different structure requirements have been observed for adequate D(1) or D(2) 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 D(2)-like receptors (K(i) value of 66nM) and the highest selectivity (49-fold D(2) vs D(1)) 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 (0.04-25mg/kg). Furthermore, this lead compound produced reduction in immobility time in the forced swimming test at a dose (0.01mg/kg) that did not modify locomotor activity. The haloperidol (0.03mg/kg), a D(2) receptor preferred antagonist, blocked the antidepressant-like effect of compound 1e.

Domaines

Neurosciences

Dates et versions

hal-00863255 , version 1 (18-09-2013)

Identifiants

Citer

Inmaculada Berenguer, Noureddine El Aouad, Sebastián Andujar, Vanessa Romero, Fernando Suvire, et al.. Tetrahydroisoquinolines as dopaminergic ligands: 1-Butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline, a new compound with antidepressant-like activity in mice.. Bioorganic and Medicinal Chemistry, 2009, 17 (14), pp.4968-80. ⟨10.1016/j.bmc.2009.05.079⟩. ⟨hal-00863255⟩
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