Mechanism of the hypotensive effect of a novel phenylpiperazine derivative, SGB-1534: antagonism at alpha 1-adrenergic and 5-HT2 receptors.

The present in vivo and in vitro experiment was designed to examine the hypotensive mechanisms of 3-[2-[4-(o-methoxyphenyl)-1-piperazinyl]ethyl]-2,4 (1H,3H)-quinazolinedione monohydrochloride (SGB-1534). The compound given orally significantly inhibited the pressor response to i.v. noradrenaline in rats and to 5-hydroxytryptamine (5-HT) in guinea-pigs but failed to block the pressor response to i.v. angiotensin II in rats. In pithed rats, SGB-1534 given i.v. had no effects on the prazosin-resistant part of the pressor effect of i.v. adrenaline, whereas it significantly inhibited the yohimbine-resistant part. In isolated guinea-pig aortae, SGB-1534 competitively inhibited the contractile response to noradrenaline with a pA2 value of 8.86, 6 times higher than prazosin. A combination of SGB-1534 with prazosin antagonized the noradrenaline effect as expected for a single class (alpha 1) of receptor. In isolated rabbit femoral arteries, SGB-1534 attenuated the contractile response to 5-HT with a pA2 value of 6.13, 400 times lower than ketanserin. A combination of SGB-1534 with ketanserin antagonized the 5-HT effect as expected for a single class (5-HT2) of receptor. In rat stomach fundus strips, SGB-1534 as well as ketanserin, even in a large dose, unlike methysergide, caused only slight inhibition of contractile response to 5-HT. These results indicate that SGB-1534 is a selective, competitive antagonist of the alpha 1-adrenoceptor and the 5-HT2 receptor, which may help to explain its antihypertensive properties.