Pharmacological Profile and Therapeutic Perspectives of Semotiadil Fumarate (SD‐3211), a Novel Benzothiazine Ca²⁺ Antagonist

Abstract

Antagonist--Ca2+ Channel-Semotiadil. Semotiadil fumarate {( + )-(R)-32-[5-methoxy-2-[3-[methy1[2-[3,4-(methylenedioxy)phenoxy]-ethyl]amino]propoxy]phenyl-W-1,4-benzothiazin-3(4H)-one hydrogen fumarate, or SD-321 l}, shown in Fig. 1, is a novel Ca2+ antagonist with a benzothiazine ring (8,26). Semotiadil exerts potent and long-lasting Ca'+ antagonistic actions, as shown by the results of in vitro and in vivo experiments. Semotiadil had intermediate tissue selectivities:it is more vasoselective than diltiazem and verapamil and more cardioselective than nifedipine. Semotiadil has been called a "second generation of

Photochemical localization of the semotiadil binding region within the cardiac Ca2+ channel α1 subunit. Comparison with the skeletal muscle counterpart

“…Hill slopes of the binding inhibition were 0.94–1.0 in cardiac channels, indicating no apparent allosteric interaction between PN200‐110 (isradipine) and semotiadil. This is in clear contrast to observations in the skeletal channel [20–22], in which semotiadil has a negative allosteric interaction with DHP, PAA and BTZ. The negative allosteric interaction was confirmed in the present work and the Hill slopes obtained were 0.63–0.67, similar to a previous report [21].…”

“…With regard to the Hill slope, 1.0 and 0.97 were obtained for semotiadil and D51‐4700 in the cardiac membranes, respectively, and 0.63 and 0.67 in the skeletal muscle membranes, suggesting no apparent allosteric interactions exist between the semotiadil analogs and PN200‐110 in the cardiac membranes but negative allosteric interactions operate in the skeletal muscle membranes. The IC 50 (2.0 μM) and Hill slope (0.63) of semotiadil for the skeletal membranes are close to the reported values in canine skeletal membranes (5.4 μM and 0.57, respectively) [21, 22]. As reference, (±)PN200‐110 inhibition in the cardiac and skeletal muscle membranes is shown in Fig.…”

“…Binding studies of semotiadil to Ca 2+ channels in skeletal muscle have been reported [20–22], but no data are available for cardiac preparations. We first tried saturation binding, using varying concentrations of tritiated analogs of semotiadil and D51‐4700 to cardiac membranes, but the level of non‐specific binding was too high for analysis.…”

“…In addition, semotiadil shows a higher selectivity for blood vessels compared with cardiac tissues than diltiazem but a lower selectivity than nifedipine [18, 19]. Semotiadil has a negative allosteric interaction with DHP, PAA and BTZ in skeletal muscle Ca 2+ channels [20–22]but equivalent data are not available for the cardiac Ca 2+ channels. Therefore, localization of the semotiadil binding site is an interesting and potentially important subject.…”

Photochemical Identification of Transmembrane Segment IVS6 as the Binding Region of Semotiadil, a New Modulator for the L-type Voltage-dependent Ca2+ Channel

“…There is no apparent similarity in the orientation of the side chains as well as in the common methoxyphenyl group between two drugs, when the phenyl ring of the benzothiazepine and 1,4-benzothiazine are overlaid by the computer. The hypothesis that the long side chain at the C-3 position of the 1,4-benzothiazine ring is a part of the pharmacophore for calcium antagonist activity (13) is supported by the fact that a similar structural component: Ar-C(R 1 R 2 )-CH 2 CH 2 CH 2 -N(Me)-CH 2 CH 2 -Ar exists in verapamil and other PAAs. It is apparent that the 1,4-benzothiazine ring of semotiadil plays an additional role that contributes to the enhanced potency.…”