Ginkgolide derivatives for photolabeling studies: preparation and pharmacological evaluation.
The terpene trilactones (TTLs), ginkgolides and bilobalide, are structurally unique constituents of Ginkgo biloba extracts, which exhibit various neuromodulatory properties. Although the TTLs are believed to be responsible for some of these effects, the specific interactions with targets in the central nervous system remain to be elucidated on a molecular level. Ginkgolides are known antagonists of the platelet-activating factor (PAF) receptor. Herein, we describe the first examination of the binding of native TTLs and their derivatives to the cloned PAF receptor, confirming that of the TTLs, ginkgolide B is the most potent PAF receptor antagonist. Ginkgolide derivatives carrying photoactivatable and fluorescent groups for the purpose of performing photolabeling have been prepared and evaluated using the cloned PAF receptor. These studies have shown that ginkgolide derivatives with aromatic photoactivatable substituents are potent PAF receptor antagonists with K(i) values of 0.09-0.79 microM and hence excellent ligands for clarifying the binding of ginkgolides to PAF receptor by photolabeling studies. Ginkgolide derivatives incorporating both fluorescent and photoactivatable groups still retained binding affinity to the PAF receptor and hence should be promising ligands for photolabeling and subsequent sequencing studies.
Department of Chemistry, Columbia University, 3000 Broadway, New York, New York 10027, USA. kn5@columbia.edu
Kristian
K
Strømgaard
D Roland
DR
Saito
Hideo
H
Shindou
Satoshi
S
Ishii
Takao
T
Shimizu
Koji
K
Nakanishi
D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D020013:Calcium Signaling / Q000187:drug effects; D006224:Cricetinae; D003517:Cyclopentanes / Q000494:pharmacology; D004224:Diterpenes; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000494:pharmacology; D046934:Ginkgolides; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D019920:Photoaffinity Labels / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011869:Radioligand Assay; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D003517:Cyclopentanes; D004224:Diterpenes; D005456:Fluorescent Dyes; D005663:Furans; D046934:Ginkgolides; D007783:Lactones; D008024:Ligands; D019920:Photoaffinity Labels; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013729:Terpenes; C039351:platelet activating factor receptor; C058295:ginkgolide C; C045856:ginkgolide B; C073710:bilobalide