MEN-10930

Abstract: A series of pseudopeptides, containing two fluorophores, such as naphthalene (N) and indole (I), and exhibiting interesting biological activity as tachykinin receptor antagonists, were investigated by electronic absorption, CD and steady‐state fluorescence experiments. In polar solvents (e.g. methanol), bioactivity is coupled with a stacked, charge‐separated complex between I and N, the amount of which depends on the stereochemical features and conformational mobility of the central scaffold in the molecules examined. This agrees with the idea that dipolar charged, spatially close, aromatic moieties are important topochemical elements in the mechanism of action of these receptor antagonists. Molecular mechanics calculations allowed us to build up hypothetical, low‐energy conformations of a few representative pseudopeptides, whose structural features are consistent with the experimental findings.

Constrained systematic search was used in an exhaustive conformational analysis of a structurally diverse set of substance P (SP) antagonists to identify a unique hypothesis for their bound conformation at the neurokinin-1 receptor. In this conformation, two aromatic groups essential for high affinity adopt a perpendicular or edge-on arrangement. This pharmacophore hypothesis for the receptor-bound conformation was used in a comparative molecular field analysis (CoMFA) of an expanded set of SP antagonists, and the predictive ability of the resulting three-dimensional quantitative structure-activity relationship (3D-QSAR) was 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 predictive r2 values equal to 0.70, 0.93, and 0.82, respectively. For comparison, the SP antagonists were forced into an alternative poorer alignment in which the two aromatic rings were parallel and then subjected to a CoMFA analysis. Both the parallel and perpendicular arrangements of the aromatic rings are seen in X-ray structures of SP antagonists and have been proposed as candidates for the receptor-bound conformation. The parallel (or stacked) conformation yielded a poorer correlation with a cross-validated r2 = 0.57, a conventional r2 = 0.90, and a predictive r2 = 0.78. Our results indicate that although both alignments could generate a reasonable CoMFA correlation, the stacked conformation is unlikely to be the receptor-bound conformation, as the covalent structure of the antagonists precludes a common geometry in which the aromatic rings are stacked.