Proposal of a new PAF pharmacophoric map by the AM1 method

PAF is a powerful phospholipid-derived autacoid involved in many pathophysiological processes. Many PAF antagonists have been synthesized and assayed for therapeutic purposes. We have synthesized derivatives (5-7), structurally related to WEB 2086 (1), which were rationally designed based on a planar PAF receptor model previously described by Bures et al. (1994; J. Chem. Inf. Comput. Sci. 24, 218-223). However, pharmacological studies revealed that derivatives (5-7) were inactive as PAF antagonists. AM1 quantum calculations of classical PAF antagonists (1-4), as well as of our derivatives (5-7), demonstrated that electronic features alone are unable to explain the lack of the activity of (5-7). These results induced us to propose a new tridimensional PAF receptor pharmacophoric map by analyzing all stable conformations obtained for derivatives (1-4). The interpoint distances (D1-D5) revealed that the lowest-energy conformers of (5-7) had similar geometries to derivatives (1-4). So, these aspects could not explain the inactivity of the compounds (6-7). The proposed model suggests that the best fit of antagonist compounds may involve the participation of a sulfur atom electron lone pair adequately oriented in relation to the plane of a N-aromatic ring present in the compounds investigated.