Tetrahydroisoquinolines functionalized with carbamates as selective ligands of D2 Dopamine Receptor

BOGADO, M. LUCRECIA; PARRAVICINI,OSCAR; ROJAS, SEBASTIAN; ANGELINA, EMILIO; ANDUJAR, SEBASTIAN; CABEDO, NURIA; SANZ, M.JESUS; LOPEZ GRESA, M. PILAR; CORTES, DIEGO; ENRIZ, RICARDO

Montevideo

Congreso; Congress of Theoretical Chemists of Latin Expression; 2016

Universidad de la Republica- Instituto Pasteur

The critical importance of both D1 and D2 receptors of dopamine signaling in Central Nervous System function makes it highly desirable to gain detailed knowledge about the structural features necessary for full agonist activity and selectivity at these receptors [1].Our research group has recently reported three new series of tetrahydroisoquinoline (THIQ) derivatives that are highly active and selective for D2 with respect to D1. In this article, a molecular modeling (MM) study allowed us to explain the higher affinity for D2 receptors displayed by the compounds of these series [2]. The group at the University of Valencia has previously reported the synthesis of 1-[(arylcarbamate)-pentyl]-1,2,3,4-THIQ derivatives [3]. These compounds possess the pharmacophoric profile of the dopamine D2 ligands, but also they have an extremely long side chain, when compared with traditional ligands of the D2 receptor. So we wonder whether this structural feature could encourage greater selectivity for the D2 receptor with respect to D1.To answer this question we conducted a MM study on this series of compounds using combined techniques (docking, MD and QTAIM calculations). Our results predict that some of these compounds would have a markedly higher affinity for D2 receptor with respect to D1. Based on these results we performed bioassays to evaluate the activity of these compounds on receptors D1 and D2. Compound 1-[(phenylcarbamate)pentyl]-6,7-dihydroxy-1,2,3,4-THIQ gave an Ki value of 91nM and 466 nM for the D2 and D1 receptor, respectively (ratio Ki D1/Ki D2=5.121), showing that it is highly selective for the D2 receptor. Clearly, the experimental results fully corroborate the results obtained from MM.