(+)-Niguldipine binds with very high affinity to Ca2+ channels and to a subtype of alpha 1-adrenoceptors.
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 Ca2+ channels and alpha-adrenoceptors. The Ki values for niguldipine were dependent on the membrane protein concentrations in the radioligand binding assay. 'True' Ki 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 (Ki: 78 nmol/l) and (-)-niguldipine (Ki: 58 nmol/l) bound with approximately equal affinity to the alpha 1-adrenoceptors ('alpha 1B') in liver cell membranes. The (+)-niguldipine alpha 1-adrenoceptor inhibition data for rat brain cortex membranes were better fitted by a two-site model. The high-affinity component ('alpha 1A') had a Ki value of 52 pmol/l in competition experiments with [3H]prazosin. The low-affinity site (alpha 1B) had 200- to 600-fold less affinity. (-)-Niguldipine was greater than 40-fold less potent at alpha 1A- but was nearly equipotent to the (+)enantiomer at alpha 1B-sites. (+)-Niguldipine was the most selective compound for discriminating alpha 1A- from alpha 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.
Boer
R
R
BYK Gulden-Lomberg GmbH, Konstanz, F.R.G.
Grassegger
A
A
Schudt
C
C
Glossmann
H
H
D000818:Animals; D002121:Calcium Channel Blockers / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D004095:Dihydropyridines / Q000378:metabolism*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D017275:Isradipine; D008099:Liver / Q000378:metabolism; D008297:Male; D009132:Muscles / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D013237:Stereoisomerism
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D007457:Iodine Radioisotopes; D011725:Pyridines; D011942:Receptors, Adrenergic, alpha; D017275:Isradipine; C054074:niguldipine