Cmr. Desantanna et al., MOLECULAR MODELING ON PLATELET-ACTIVATING-FACTOR (PAF) AND NEW PROPOSED PAF ANTAGONISTS, International journal of quantum chemistry, 60(5), 1996, pp. 1069-1080
Platelet-activating factor (PAF) is an autacoid derived from cellular
membrane phospholipids in response to chemical or physical stimuli. It
has been identified as 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphocholin
e; the alkyl group is composed of 16 or 18 carbon atoms in human cells
. PAF can cause a series of pathophysiological effects, related to inf
lammatory and allergic diseases such as asthma, gastric ulcerations, t
ransplant rejections, psoriasis, cerebral, renal, and myocardial ische
mia. As PAF biological action is a result of interactions with specifi
c receptors on target cells, several specific PAF receptor antagonists
have been proposed for therapeutic control of the pathological states
in which PAF is implicated. In this work we have calculated at AMI le
vel 16 conformations of a model (alkyl = octyl) of (R)-PAF. We have us
ed these conformations and calculated structures of two hetrazepines (
WEB 2086 and E 6123), FR 128998 and RP 59227, known antagonists of PAF
activity currently under development, to test a recently proposed pha
rmacophore map. Our results suggest that the model is too rigid. Havin
g mind, we used the pharmacophore model to evaluate the potential acti
vity of a new series of proposed PAF receptor antagonists based on bic
yclo[3.3.0]-2-oxaoctane. The results were used to decide which compoun
ds should receive priority in synthesis. The synthetic results and pha
rmacological profiles of the new derivatives will be published elsewhe
re. (C) 1996 John Wiley & Sons, Inc.