Theoretical and experimental study of 1-[(arylcarbamate)-pentyl]-1,2,3,4- tetrahydroisoquinoline derivatives acting as highly selective ligands of the D2 dopamine receptor

PARRAVICINI, OSCAR ; ANDUJAR, SEBASTIAN ANTONIO; LOPEZ-GRESA, M. PILAR; ROJAS, SEBASTIAN; CABEDO, NURIA; CORTES, DIEGO; BOGADO, MARIA LUCRECIA; ANGELINA, EMILIO LUIS; SANZ, MARÍA JESÚS; ENRIZ, RICARDO DANIEL

Montevideo

Congreso; XLII Congreso de Químicos Teóricos de Expresión Latina (QUITEL); 2016

Universidad de la República

p { margin-bottom: 0.1in; direction: ltr; color: rgb(0, 0, 10); line-height: 120%; text-align: left; }p.western { font-family: "Calibri",serif; font-size: 11pt; }p.cjk { font-family: "Droid Sans Fallback"; font-size: 11pt; }p.ctl { font-family: "DejaVu Sans"; font-size: 11pt; }The critical importance of both D1 and D2receptors of dopamine signaling in Central Nervous System functionmakes it highly desirable to gain detailed knowledge about thestructural features necessary for full agonist activity andselectivity at these receptors [1].Our research group has recently reported three new series oftetrahydroisoquinoline (THIQ) derivatives that are highly active andselective for D2 with respect to D1. In thisarticle, a molecular modeling (MM) study allowed us to explain thehigher affinity for D2 receptors displayed by thecompounds of these series [2]. The group at the University ofValencia has previously reported the synthesis of1-[(arylcarbamate)-pentyl]-1,2,3,4-THIQ derivatives [3]. Thesecompounds possess the pharmacophoric profile of the dopamine D2ligands, but also they have an extremely long side chain, whencompared with traditional ligands of the D2 receptor. Sowe wonder whether this structural feature could encourage greaterselectivity for the D2 receptor with respect to D1.To answer this question we conducted a MM study on this series ofcompounds using combined techniques (docking, MD and QTAIMcalculations). Our results predict that some of these compounds wouldhave a markedly higher affinity for D2 receptor withrespect to D1. Based on these results we performedbioassays to evaluate the activity of these compounds on receptors D1and D2. Compound1-[(phenylcarbamate)pentyl]-6,7-dihydroxy-1,2,3,4-THIQ gave an Kivalue of 91nM and 466 nM for the D2 and D1 receptor,respectively (ratio Ki D1/Ki D2=5.121), showingthat it is highly selective for the D2 receptor. Clearly,the experimental results fully corroborate the results obtained fromMM.p { margin-bottom: 0.1in; direction: ltr; color: rgb(0, 0, 10); line-height: 120%; text-align: left; }p.western { font-family: "Calibri",serif; font-size: 11pt; }p.cjk { font-family: "Droid Sans Fallback"; font-size: 11pt; }p.ctl { font-family: "DejaVu Sans"; font-size: 11pt; }[1]P. Seeman, M. Watanabe, D. Grigoriadis, J. L. Tedesco, S. R. George,U. Svensson, J. L. G. Nilsson, and J. L. Neumeyer, ?Dopamine D2receptor binding sites for agonists. A tetrahedral model? , Mol.Pharmacol.,28(1985)391 ? 399.[2]J. Parraga, S. A. Andujar, S. Rojas, L. J. Gutierrez, N. El Aouad, M.J. Sanz, R. D. Enriz, N. Cabedo, and D. Cortes, ?Dopaminergicisoquinolines with hexahydrocyclopenta[ij]-isoquinolines as D2-likeselective ligands?, Eur.J. Med. Chem.122(2016) 27-42.[3]A. Galán, L. Moreno, J. Párraga, Á. Serrano, M. J. Sanz, D.Cortes, and N. Cabedo, ?Novel isoquinoline derivatives asantimicrobial agents?, Bioorgan.Med. Chem.21(2013) 3221?3230.