European Journal of Pharmacology - Molecular Pharmacology Section. 189 (1990) 59-70 59 Elsevier EJPMOL 90093 Optically active benzamides as predictive tools for mapping the dopamine D 2 receptor Didier Rognan ", Pierre Sokoloff 2 Andr6 Mann ~, Marie-Pascale Martres 2 Jean-Charles Schwartz 2, Jean Costentin 3 and Camille-Georges Wermuth i Centre de Neurochimie du CNRS. D@artement de Pharmacochimie Mof~cutaire. 67084 Strasbourg. France, 2 Unit~ 109 de Neurobiologie. Centre Paul Broca de I'INSERM. 75014 Paris, France, and ~ IJnit~ de Neuropsychephamracologie Exp#rimentale, UER de M~dectne, 76800 St-Etienne du Rou~ray, France Received9 March 1990, accepted i7 April 1990 Substituent variations on th~ pyrrolidinyl nitrogen of sulphide, a selective D 2 dopamine antagonist, showed that in vitro and in vivo activities are concentrated in the (S) optical series for N-alkyl analogs and in the (R) series for N-benzyl analogs. To account for these unusual structure-activi D, relationships, a pharmacophoric model was built from the crystallographic structure of (-)piquindone and extended to 14 other D 2 antagonists. This model considers the lone pair orientation of the basic nitrogen rather than its spatial location. Two distinct active conformations for benzamides were defined, corresponding to the (S) and (R) series. An extended pharmacophore is then propo~d involving four main anchoring areas: (i) an aromatic site Ar h (ii) a tertiary nitrogen with its lone pair orthogonal to the Ar1 plane, ('ni) a dipole A1 coplanar to the Ar1 ring and (iv) three sites for the N-substituent, including a small hydrophobie pocket and two differen~ aromatic binding sites Ar 2 and Ar~. To probe the predictive value of this model, structures were designed and several compounds were synthesized and tested as inhibitors of [Jzsf]iodosulpride binding to rat striatal membranes and as antagonists of apomorphine-induced stereotyped behavior in lrfice. Dopamine D~ receptor; Computer graphics; Benzamides; StereoselectNity 1. Introduction Among dopamine antagonists, sulpiride (fig. 1) and other benzamides are characterized ~y a high selectivity for the DE receptor, their affinity for the D~ receptor or non-dopamine receptors being generally negligible (Trabucchi et al. 1975; Elliot et al., 1977; Jenner and Marsden, 1979; Kebabian and Calne, 1979). In addition, most benzamides seem to display a unique pharmacological profile in comparison with other dopamine D 2 antago- nists, in vivo and in vitro, tentatively attributed to Correspondence to: Andr~ Mann, Centre de Neurochimie du CNRS, De,oartement de Pharmacochimie Moltcalaire. 5 rue B. Pascal, 67084 Strasbourg Cedex.,France. their unique abi*.ity to distinguish two D 2 receptor subtypes (Martres et ak, 1984; Schwartz el al. 1984; Sokoloff et al., 1984, 1985). This h)~pothesis can be related to the low propensity of benz- amides to induce neurological side effects (ex- trapyramidal syndromes, tardive dyskinesia) and to their unique beneficial effect on negative symp- toms in schizophrenia (Jenner and Marten, 1979; Munk-Andersen et aL, 1982; Alfrcdsson et al., 1985). Hence. the possibility to increase the specificity and discriminating properties of benz- amides by the design of novel compounds prompted us to anal)~e their active conformation and to compare it to that of other D2 m,,tagonists. Structure-activity relationships on suipiride de- rivatives (?.-substituted pyrrolidinyl benzamides) 0922-4106/90/$03.50 © 1990 El~'der Science P'~blishers B.V. (Biom~d~c~J Division)