(+)-Niguldipine binds with very high affinity to Ca 2+ channels and to a subtype of α1-adrenoceptors

Abstract

The enantiomers of the 1,4-dihydropyridine (DHP) niguldipine (3-methyl-5-[3-(4,4-diphenyl-1-piperidinyl)-propyl]-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate-hydrochloride) were investigated with respect to their interaction with 1,4-DHP receptors on L-type Ca 2+ channels and α-adrenoceptors. The K i values for niguldipine were dependent on the membrane protein concentrations in the radioligand binding assay. ‘True’ K i values (at extrapolated ‘zero’ membrane protein) were determined with guinea-pig membranes for (+)-niguldipine and were found to be 85 pmol/l for the 1,4-DHP receptor of skeletal muscle, 140 pmol/l for that of brain and 45 pmol/l for that of heart. (−)-Niguldipine was approximately 40 times less potent. (+)-Niguldipine (K i: 78 nmol/l) and (−)-niguldipine (K i: 58 nmol/l) bound with approximately equal affinity to the α 1-adrenoceptors (‘α 1 B ’) in liver cell membranes. The (+)-niguldipine α 1-adrenoceptor inhibition data for rat brain cortex membranes were better fitted by a two-site model. The high-affinity component (‘α 1 A ’) had a K i value of 52 pmol/l in competition experiments with [ 3H]prazosin. The low-affinity site ( α 1B) had 200- to 600-fold less affinity. (−)-Niguldipine was > 40-fold less potent at α 1A- but was nearly equipotent to the (+)-enantiomer at α 1B-sites. (+)-Niguldipine was the most selective compound for discriminating α 1A- from α 1B-adrenoceptors and is a novel prototype for 1,4-DHPs which bind with nearly equal affinity to skeletal muscle and brain or heart 1,4-DHP receptors.