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  • Title: Allosteric interaction of semotiadil fumarate, a novel benzothiazine, with 1,4-dihydropyridines, phenylalkylamines, and 1,5-benzothiazepines at the Ca(2+)-channel antagonist binding sites in canine skeletal muscle membranes.
    Author: Nakayama K, Nozawa Y, Fukuta Y.
    Journal: J Cardiovasc Pharmacol; 1994 May; 23(5):731-40. PubMed ID: 7521455.
    Abstract:
    We assessed the binding characteristics of a benzothiazine Ca(2+)-channel antagonist, semotiadil, in canine skeletal muscle membranes. Semotiadil inhibited binding of (+)-[3H]PN 200-110 (maximum inhibition 80%), and almost completely inhibited binding of both (-)-[3H]desmethoxyverapamil and D-cis-[3H]diltiazem to their specific binding sites with an IC50 value of 0.2-2 microM and a Hill slope of 0.6-0.9. Saturation isotherm and dissociation kinetic studies suggest that semotiadil acts as a noncompetitive inhibitor at the 1,4-dihydropyridine, phenylalkylamine, and benzothiazepine (BTZ) recognition sites in the L-type Ca2+ channel: (a) Scatchard analysis showed that semotiadil decreased maximum binding (Bmax) of the three classes of Ca2+ channel antagonists, while causing a slight increase in the equilibrium dissociation constant (Kd) in the case of (+)-[3H]PN 200-110 binding or no significant change in Kd values for binding of (-)-[3H]desmethoxyverapamil and D-cis-[3H]diltiazem to their specific binding sites; and (b) dissociation kinetics of the (+)-[3H]PN 200-110 and D-cis-[3H]diltiazem bindings were accelerated by semotiadil. These results suggest that semotiadil has a strong negative allosteric interaction with three classes of Ca2+ channel antagonists, including 1,4-dihydropyridines, phenylalkylamines, and BTZ at their specific binding sites.
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