B-HT 958, a new α-adrenoceptor agonist with a high pre/postsynaptic activity ratio

Summary

B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo [5,4-d] azepine) was a potent agonist at presynaptic and a less potent agonist at postsynaptic α-adrenoceptor sites. Presynaptically this was shown in pithed rats by the inhibition of tachycardia evoked by sympathetic nerve stimulation (0.2 Hz). The 50% inhibitory dose (ID 50) was 0.3 mg/kg i.v. Moreover in isolated perfused cat hearts, the drug inhibited the tachycardia and the outflow of noradrenaline induced by sympathetic nerve impulses. These effects of B-HT 958 were antagonized by phentolamine or yohimbine. At postsynaptic sites high doses of B-HT 958 increased the blood pressure of decentralized rats. The dose which increased pressure by 30 mm Hg (PD30) was 46.3 mg/kg i.v. This effect was antagonized by rauwolscine 5 mg/kg i.v. After pretreatment with reserpine (7.5 mg/kg i.p., 18 h) B-HT 958 proved much more potent (PD30=0.6 mg/kg i.v.), and its effect was strongly antagonized by yohimbine but hardly by prazosin. The dose of yohimbine which shifted the dose-response curve of B-HT 958 by the factor of 10 (D 10) to the right was 1.8 mg/kg i.v., the corresponding dose of prazosin was 1,900 mg/kg i.v. (extrapolated).

B-HT 958 showed also α-adrenoceptor blocking properties. This was demonstrated presynaptically in pithed rats by the drug-induced augmentation of tachycardia elicited by electrical stimulation at high frequency (6.4 Hz). At postsynaptic sites B-HT 958 antagonized the blood pressure increase caused by B-HT 920 (α₂; D 10=1.1 mg/kg i.v.) but not that caused by methoxamine (α₁).

It is concluded that B-HT 958 is a partial agonist at peripheral α₂-adrenoceptors. In doses of about 1 mg/kg and with low frequency sympathetic stimulation (<6.4 Hz) it acts presynaptically as agonist; in this dose the drug acts postsynaptically mainly as antagonist.