Semotiadil

To clarify the recognition site of (S)-semotiadil in the Na⁺ channels, we employed photoaffinity labeling with (S)-[³H]-D51-4700, an azidophenyl derivative of (S)-semotiadil, to Na⁺ channel preparations from rat brains and porcine hearts, and the results were compared with those by (R)-enantiomer to skeletal muscle Ca²⁺ channel.Protease-digestion of the photolabeled Na⁺ channels followed by quant. immunoprecipitation assay using a site-directed antibody, revealed that 10- and 13- kDa fragments of brain and cardiac Na⁺ channels, resp., were located within the regions including IVS6.These regions are corresponding to the 8.3 kDa fragment photolabeled by (R)-[³H]-D51-4700 in the skeletal muscle Ca²⁺ channel.Interestingly, however, the photoincorporation of (S)-[³H]-D51-4700 into the Na⁺ channel was 2-3 times higher than that of (R)-isomer; and visa versa in the Ca²⁺ channels.

Calcium antagonists are known to exert antiplatelet activity. Semotiadil fumarate (SD-3211), a new benzothiazine, was therefore examined for its antiplatelet activity. The inhibitory activity on adenosine diphosphate (ADP)-, collagen-, arachidonic acid (AA)-, and platelet activating factor (PAF)-induced platelet aggregation after the 1-, 30-, 60- and 120-min incubation at concentrations ranging from 1 x 10(-3), 1 x 10(-4), 1 x 10(-5), 1 x 10(-6) and 1 x 10(-7) was examined. The data were compared with those using diltiazem, nifedipine and amlodipine under identical conditions in blood from eight healthy volunteers (four males, four females; aged 23-36 years) and eight hypertensive patients (four males, four females; aged 31-46 years). Semotiadil showed a dose-dependent inhibition of platelet aggregation in vitro with all the agents examined. Using the various aggregation-inducing agents, the dose-dependent inhibitory action was comparable for all the compounds tested. The antiaggregatory potency was in the order diltiazem, semotiadil, amlodipine and nifedipine. The incubation period did not significantly affect the antiaggregatory effect. No difference between platelets derived from healthy volunteers and hypertensive patients was noted. These findings indicate potent antiplatelet activity of the new calcium antagonist semotiadil.