CALCIUM ANTAGONISTIC AND BINDING-PROPERTIES OF SEMOTIADIL (SD-3211), A BENZOTHIAZINE DERIVATIVE ASSESSED IN CEREBRAL AND CORONARY-ARTERIES

The present experiments were undertaken to elucidate Ca2+ antagonistic and binding properties of semotiadil and its (S)-(-)-enantiomer (SD-3212) in plausible clinical target tissues such as cerebral and coronary arteries. Semotiadil was about six times more potent than D-cis-diltiazem for Ca2+ antagonistic action, with a long-lasting and wide spectrum of inhibitory effects on contraction of dog cerebral arteries elicited by various spasmogens and mechanical stretch. Semotiadil exhibited a weak, negative, and heterotropic allosteric effect on (+)-[H-3]PN 200-110 binding to pig coronary artery membranes: Scatchard analysis of saturation isotherms indicated that semotiadil increased the equilibrium dissociation constant (K(d)) of (+)-[H-3]PN-200-110 binding without causing a significant change in the maximum binding density (B(max)). Furthermore, semotiadil significantly increased the dissociation rate (k-1) of (+)-[H-3]PN 200-110 from the specific binding site. The enhanced binding of (+)-[H-3]PN 200-110 to the coronary artery caused by D-Cis-diltiazem was attenuated when semotiadil was present, whereas binding inhibited by verapamil was not affected in the presence of semotiadil. The results suggest that semotiadil exerts a potent Ca2+ antagonistic action by binding to a site in the Ca2+ channel distinct from the 1,4-dihydropyridine recognition site and interacts with the 1,4-dihydropyridine binding site in a negative, heterotropic, allosteric manner.