Comparative behavioral, neurochemical and pharmacological activities of dihydropyridine calcium channel activating drugs

S. K. O'Neill, D. W. McKay, N. Campbell, Christopher Triggle, M. Crowley, G. T. Bolger

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Abstract

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 > (±)-BAY K 8644 >> (+)-S-202-791 > (±)-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, (+)-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. Dihydropyridine calcium channel activators produced increases (8-56%) in neurotransmitter metabolites in the striatum but not in the somatosensory cortex of mouse brain. These results indicate that dihydropyridine calcium channel activators of varying structure can, induce behaviors in mice, an ability which resides in the calcium channel activating enantiomer, and bind to dihydropyridine receptors in either a simple or complex manner. As such, dihydropyridine receptors may mediate the behaviors and the brain region-specific changes in neurotransmitter metabolites that occur subsequent to activation of neuronal calcium channels.

Original languageEnglish
Pages (from-to)905-912
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume253
Issue number3
Publication statusPublished - 1990
Externally publishedYes

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ASJC Scopus subject areas

  • Pharmacology

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