Substituent variations on the pyrrolidinyl nitrogen of sulpiride, a selective D2 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-activity relationships, a pharmacophoric model was built from the crystallographic structure of (-)piquindone and extended to 14 other D2 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 proposed involving four main anchoring areas: (i) an aromatic site Ar1, (ii) a tertiary nitrogen with its lone pair orthogonal to the Ar1 plane, (iii) a dipole delta 1 coplanar to the Ar1 ring and (iv) three sites for the N-substituent, including a small hydrophobic pocket and two different aromatic binding sites Ar2 and Ar3. To probe the predictive value of this model, structures were designed and several compounds were synthesized and tested as inhibitors of [125I]iodo-sulpiride binding to rat striatal membranes and as antagonists of apomorphine-induced stereotyped behavior in mice.