COMPARISON OF 5-HT(1A) AND DOPAMINE-D(2) PHARMACOPHORES - X-RAY STRUCTURES AND AFFINITIES OF CONFORMATIONALLY CONSTRAINED LIGANDS

Conformational and molecular mechanics studies of a new series of tric yclic ligands with affinity for either the dopamine D2 receptor or the 5-HT1A receptor, or both, has enabled us to elaborate considerably on previous pharmacophore models for these receptors. The new tricyclic ligands are either angular, 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole d erivatives, or linear, 2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole deriva tives; they have either cis or trans ring junctions, and many of the l igands are resolved. In order to have X-ray crystal coordinates for ev ery structural type, two additional crystal structures were determined : 14a, the trans-(+/-)-6-hydroxy-3-(n-propyl) angular derivative as th e hydrochloride, and ro-8-methoxy-2-(2-propenyl)-naphth[2,1-b]azetidin e hydrochloride (16d). Several recently reported imidazoquinolinones w ith dopaminergic and serotonergic activities were also used in develop ing the models as were other known ligands which are conformationally constrained. A new method for determining intrinsic activity at the D2 receptor made consistent and reliable estimates of dopamine agonist, partial agonist, and antagonist activities available. The models expla in these activities in terms of the 3-dimensional structural features of the ligands and their probable orientations at the D2 receptor site . They also explain why allyl and propyl analogs of some structures ha ve very different affinities while affinities are quite similar for al lyl and propyl analogs of other structures; at both receptors a partic ular orientation of the amine substituent in the binding site correlat es with preference for allyl over propyl derivatives. Suggestions are made for enhancing selectivity at the 5-HT1A receptor or at the dopami ne D2 receptor. An angular, cis, (3aR,9bS), 2-propyl, 9-hydroxy, 3-(n- propyl) analog should be selective for the 5-HT1A receptor. A linear, trans, (3aR,9aS), 7-hydroxy, 1-(2-propenyl) analog should be selective for the dopamine D2 receptor, and would be predicted to be an antagon ist.