[3H]HOE166 Defines a Novel Calcium Antagonist Drug Receptor--distinct from the 1,4 Dihydropyridine Binding Domain

Overview

Journal Naunyn Schmiedebergs Arch Pharmacol

Specialty Pharmacology

Date 1989 Dec 1

PMID 2561307

Citations 2

Authors

A Grassegger

J Striessnig

M Weiler

H G Knaus

H Glossmann

Affiliations

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Abstract

Benzothiazinones represent a novel class of drugs which block voltage-dependent L-type calcium channels in different tissues. [3H]HOE166 (R-(+-)-3,4-dihydro-2-isopropyl-4-methyl-2-[2-[4-[4-[2- (3,4,5-trimethoxyphenyl)ethyl]-piperazinyl]butoxy]phenyl]-2H-1,4- benzothiazin-3-on-dihydrochloride; approximately 57 Ci/mmol) a potent optically pure benzothiazinone was employed to characterize receptors associated with skeletal muscle transverse tubule calcium channels. [3H]HOE166 reversibly labels the membrane-bound calcium channels with high affinity (Kd = 0.36 +/- 0.05 nM; Bmax = 18.2 +/- 3.3 pmol/mg of membrane protein; means +/- SD, n = 13), HOE166 (Ki = 0.76 nM) is 29-fold more potent than the respective (S)-enantiomer (Ki = 22.1 nM). Binding is inhibited by divalent and trivalent cations (Cd2+ and La3+ being most potent) and other calcium channel drugs (1,4 dihydropyridines, phenylalkylamines, benzothiazepines). High affinity [3H]HOE166 binding activity is maintained (Kd = 4.5-9.0 nM) after solubilization and purification (554-1350 pmoles/mg of protein) of the calcium channel complex from transverse-tubule membranes. The following data support our recent claim (Striessnig et al. 1985, 1988) that HOE166 labels a domain on L-type calcium channels which is distinct from that defined by 1,4 dihydropyridines, phenylalkylamines or benzothiazepines: (1) All 1,4 dihydropyridine-, phenylalkylamine- and benzothiazepine-receptor-selective drugs tested are only very weak inhibitors of [3H]HOE166 binding. (2) (+)-PN200-110 only partially inhibits [3H]HOE166 binding to the purified calcium channel complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Citing Articles

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Glossmann H, Zech C, Striessnig J, Staudinger R, Hall L, Greenberg R Br J Pharmacol. 1991; 102(2):446-52.

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Kinetic modulation of guinea-pig cardiac L-type calcium channels by fendiline and reversal of the effects of Bay K 8644.

Schreibmayer W, Tripathi O, Tritthart H Br J Pharmacol. 1992; 106(1):151-6.

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