Chemical and biochemical characterization of lignan analogs as novel PAF receptor antagonists.
Various derivatives and isosteres of neolignans of the 2,5-diaryl tetrahydrofuran type have been synthesized as antagonists of platelet-activating factor (PAF). A detailed analysis of their structure-activity relationship (SAR) has revealed a clear preference for an asymmetrical molecular configuration with a high degree of stereo and chiral specificity associated with greater potency. The trans-2S,5S enantiomers are generally 10-200 times more potent in vitro than their corresponding cis or trans-2R,5R isomers. A similar stereochemical preference is indicated by the recently reported PAF antagonist MK-287 which has undergone clinical evaluation. An azido derivative L-662,025 has been characterized as a photolabile irreversible antagonist of PAF for the investigation of solubilized and partially purified PAF binding proteins from cell membranes. The biological justification for concomitant inhibition of both PAF receptor and 5-lipoxygenase in inflammation is well recognized. The feasibility of developing such dual-functional agents has been demonstrated by a group of dithiolane analogs of neolignans and several derivatives of futoenone.
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Department of Chemistry, University of Virginia, Charlottesville 22901.
D000818:Animals; D017705:Lignans; D008031:Lignin / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D043562:Receptors, G-Protein-Coupled; D013329:Structure-Activity Relationship
D017705:Lignans; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D008031:Lignin