DERIVATION OF A 3-DIMENSIONAL PHARMACOPHORE MODEL OF SUBSTANCE-P ANTAGONISTS BOUND TO THE NEUROKININ-1 RECEPTOR

Constrained systematic search was used in an exhaustive conformational analysis of a structurally diverse set of substance P (SP) antagonist s to identify a unique hypothesis for their bound conformation at the neurokinin-1 receptor. In this conformation, two aromatic groups essen tial for high affinity adopt a perpendicular or edge-on arrangement. T his pharmacophore hypothesis for the receptor-bound conformation was u sed in a comparative molecular field analysis (CoMFA) of an expanded s et of SP antagonists, and the predictive ability of the resulting thre e-dimensional quantitative structure-activity relationship (3D-QSAR) w as evaluated against a test set of SP antagonists different from those in the training set. This CoMFA model based on the Constrained Search alignment yielded significant cross-validated, conventional, and pred ictive r(2) values equal to 0.70, 0.93, and 0.82, respectively. For co mparison, the SP antagonists were forced into an alternative poorer al ignment in which the two aromatic rings were parallel and then subject ed to a CoMFA analysis. Both the parallel and perpendicular arrangemen ts of the aromatic rings are seen in X-ray structures of SP antagonist s and have been proposed as candidates for the receptor-bound conforma tion. The parallel(or stacked) conformation yielded a poorer correlati on with a cross-validated r(2) = 0.57, a conventional r(2) = 0.90, and a predictive r(2) = 0.78. Our results indicate that although both ali gnments could generate a reasonable CoMFA correlation, the stacked con formation is unlikely to be the receptor-bound conformation, as the co valent structure of the antagonists precludes a common geometry in whi ch the aromatic rings are stacked.