Potent enhancement of (/sup 3/H)nitrendipine binding in rat cerebral cortical and cardiac homogenates: a putative mechanism for the action of MDL 12,330A

Journal Article · Sat Jun 01 04:00:00 EDT 1985 · J. Pharmacol. Exp. Ther.; (United States)

OSTI ID:5253960

Lee, H R; Jaros, J A; Roeske, W R; Wiech, N L; Ursillo, R; Yamamura, H I

(/sup 3/H)Nitrendipine ((/sup 3/H)NTD), a specific high-affinity calcium channel antagonist, was used to label dihydropyridine binding sites associated with calcium channels in rat cerebral cortical and cardiac homogenates. A novel lactamimide compound, MDL 12,330A, has been shown previously to have negative inotropic and chronotropic effects in isolated working guinea-pig hearts and these effects are reversed by the administration of calcium. MDL 12,330A is potent in enhancing (/sup 3/H)NTD binding in membranes prepared from the cerebral cortex and the heart, with EC50 values of 6.1 X 10(-8) and 3.4 X 10(-8) M, respectively, at 37 degrees C. This allosteric effect by MDL 12,330A is similar to that produced by a known calcium channel antagonist, d-cis diltiazem, which has been shown previously to enhance (/sup 3/H)NTD binding at 37 degrees C. The extent of enhancement by MDL 12,330A depends on incubation temperature (37 degrees C greater than 25 degrees C greater than 0 degrees C). The mechanism of this enhancement by MDL 12,330A is due to a decrease in the dissociation rate constant of the dihydropyridine-calcium channel supramolecular complex. MDL 12,330A is the most potent drug thus far examined which demonstrates the enhancement of (/sup 3/H)NTD binding.

• Research Organization: Univ. of Arizona College of Medicine, Tuscon
• OSTI ID: 5253960
• Journal Information: J. Pharmacol. Exp. Ther.; (United States), Journal Name: J. Pharmacol. Exp. Ther.; (United States) Vol. 3; ISSN JPETA
• Country of Publication: United States
• Language: English

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550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AFFINITY
ALKALINE EARTH METALS
ANIMALS
AZINES
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL HALF-LIFE
BODY
BRAIN
CALCIUM
CARDIOVASCULAR SYSTEM
CELL CONSTITUENTS
CELL MEMBRANES
CENTRAL NERVOUS SYSTEM
CEREBRAL CORTEX
CEREBRUM
CHEMICAL BONDS
ELEMENTS
HEART
HETEROCYCLIC COMPOUNDS
IMINES
IN VITRO
ISOTOPE APPLICATIONS
KINETICS
LABELLED COMPOUNDS
MAMMALS
MEMBRANES
METALS
MUSCLES
MYOCARDIUM
NERVOUS SYSTEM
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PYRIDINES
RATS
REACTION KINETICS
RODENTS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
VERTEBRATES