Proposal of a new PAF pharmacophoric map by the AM1 method

PAF is a powerful phospholipid-derived autacoid involved in many pathophysi ological processes. Many PAF antagonists have been synthesized and assayed for therapeutic purposes. We have synthesized derivatives (5-7), structural ly related to WEB 2086 (1), which were rationally designed based on a plana r PAF receptor model previously described by Bures et al. (1994; J. Chem. I nf. Comput. Sci. 24, 218-223). However, pharmacological studies revealed th at derivatives (5-7) were inactive as PAF antagonists. AMI quantum calculat ions of classical PAF antagonists (1-4), as well as of our derivatives (5-7 ), demonstrated that electronic features alone are unable to explain the la ck of the activity of (5-7). These results induced us to propose a new trid imensional PAF receptor pharmacophoric map by analyzing all stable conforma tions obtained for derivatives (1-4). The interpoint distances (D1-D5) reve aled that the lowest-energy conformers of (5-7) had similar geometries to d erivatives (1-4). So, these aspects could not explain the inactivity of the compounds (6-7). The proposed model suggests that the best fit of antagoni st compounds may involve the participation of a sulfur atom electron lone p air adequately oriented in relation to the plane of a N-aromatic ring prese nt in the compounds investigated. (C) 1999 Elsevier Science B.V. All rights reserved.