title: Proposal of a new PAF pharmacophoric map by the AM1 method.
abstract: 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.
authors.affiliation: LASSBio, Departamento de Fármacos, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, P.O. Box 68006, Rio de Janeiro, RJ 21944-970, Brazil.
authors.forename: C R
authors.initials: CR
authors.lastname: Rodrigues
authors.forename: R B
authors.initials: RB
authors.lastname: de Alencastro
authors.forename: E J
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: C A
authors.initials: CA
authors.lastname: Fraga
mesh_terms: D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D011789:Quantum Theory; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D001381:Azepines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C039351:platelet activating factor receptor; C052518:WEB 2086