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 00:00:00 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), Vol. 3
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES
PYRIDINES
CHEMICAL BONDS
AFFINITY
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL HALF-LIFE
CALCIUM
CELL MEMBRANES
CEREBRAL CORTEX
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CENTRAL NERVOUS SYSTEM
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KINETICS
LABELLED COMPOUNDS
MAMMALS
MEMBRANES
METALS
MUSCLES
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ORGANIC NITROGEN COMPOUNDS
ORGANS
REACTION KINETICS
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550201* - Biochemistry- Tracer Techniques