Comparative behavioral, neurochemical and pharmacological activities of dihydropyridine calcium channel activating drugs.
The behavioral (deficits in motor function in mice), neurochemical (affinity for mouse brain membrane dihydropyridine receptors, effects on neurotransmitter/metabolite levels in mice) and pharmacologic (effect on the contractile activity of guinea pig ileal longitudinal smooth muscle) properties of the calcium channel activators (+/-)-BAY K 8644, (+/-)-202-791 (and their corresponding channel activating and antagonist enantiomers) and CGP-28392 were investigated and compared. The calcium channel activating enantiomers (-)-S-BAY K 8644, (+)-S-202-791 and (+/-)-BAY K 8644, (+/-)-202-791 and CGP-28392 produced a dose-dependent impairment of rotarod ability and decreases in motor activity in mice with the following order of potency: (-)-S-BAY K 8644 greater than (+/-)-BAY K 8644 much greater than (+)-S-202-791 greater than (+/-)-202-791 = CGP-28392. The calcium channel antagonists (+)-R-BAY K 8644 and (-)-R-202-791 were behaviorally inactive but blocked the behavioral effects of (-)-S-BAY K 8644. The binding of dihydropyridine calcium channel activator and antagonist enantiomers to mouse brain membranes was described by both one and two site models. (-)-S-BAY K 8644, (+/-)-BAY K 8644, (+)-S-202-791 and CGP-28392 produced contractions in partially depolarized (15 mM K+) strips of guinea pig ileal longitudinal smooth muscle which differed in the degree of maximum contraction obtained. (+)-R-BAY K 8644 and (-)-R-202-791 inhibited potassium-induced contractions (80 mM K+) in guinea pig ileal longitudinal smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
O'Neill
S K
SK
Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.
McKay
D W
DW
Campbell
N
N
Triggle
C R
CR
Crowley
M
M
Bolger
G T
GT
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000378:metabolism / Q000494:pharmacology*; D002395:Catecholamines / Q000032:analysis; D002851:Chromatography, High Pressure Liquid; D004095:Dihydropyridines / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009539:Nicotinic Acids / Q000378:metabolism / Q000494:pharmacology; D009543:Nifedipine / Q000378:metabolism / Q000494:pharmacology; D010069:Oxadiazoles; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002120:Calcium Channel Agonists; D002395:Catecholamines; D004095:Dihydropyridines; D009539:Nicotinic Acids; D010069:Oxadiazoles; D011725:Pyridines; C049834:PN 202-791; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C040525:CGP 28392; D009543:Nifedipine