title: Calcium channel receptor binding studies for diltiazem and its major metabolites: functional correlation to inhibition of portal vein myogenic activity.
abstract: Pharmacologically distinct but allosterically interacting calcium channel antagonist binding sites have recently been identified using radiolabeled dihydropyridine derivatives (e.g., [3H]nitrendipine) and the benzothiazepine [3H]diltiazem. Whereas the functional significance of the dihydropyridine calcium channel antagonist receptor is well documented, it remains to be established whether drug interactions with the recognition site for [3H]diltiazem within the slow calcium channel or the allosteric interaction of the diltiazem binding site with the dihydropyridine receptor are of physiological significance. In a study of structure-activity relationships, we therefore examined the effects of diltiazem and five of its analogs on the binding of [3H]diltiazem and [3H]nitrendipine to the rat cerebral cortex. In parallel, we studied the effects of these drugs on the spontaneous myogenic contractions of the rat portal vein, a functional test of calcium antagonism. The diltiazem analogs used in this study correspond to its major metabolites in humans, i.e., N-desmethyl-(MA, desacetyl-(M1), N-desmethyl, desacetyl-(M2), O-desmethyl, desacetyl (M4), N-desmethyl, O-desmethyl, desacetyl-diltiazem (M6). Unlabeled diltiazem inhibited [3H]diltiazem binding at 37 degrees C with a pIC50 [-log IC50 (M)] of 6.87. pIC50 values for M1, MA, M2, M4, and M6 were 6.72, 6.49, 6.03, 5.51, and 5.33, respectively. pIC50 values for these drugs on [3H]diltiazem binding were significantly correlated (p less than 0.01) with their pEC50 values for enhancement of [3H]nitrendipine binding to cerebral cortical membranes at 37 degrees C. Maximal enhancement of [3H]nitrendipine binding by diltiazem, M1, MA, M2, M4, and M6 was 73, 50, 9.7, 11, 12, and 52%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels; D002540:Cerebral Cortex / Q000378:metabolism*; D004110:Diltiazem / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D007473:Ion Channels / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009568:Nitrendipine / Q000378:metabolism; D011169:Portal Vein / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D007473:Ion Channels; D011978:Receptors, Nicotinic; D009568:Nitrendipine; D004110:Diltiazem; D002118:Calcium