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

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 alpha-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 (ID50) 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 (PD 30) 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 (PD 30 = 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 (D10) to the right was 1.8 mg/kg iv., the corresponding dose of prazosin was 1,900 mg/kg i.v. (extrapolated). B-HT 958 showed also alpha-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 (alpha 2; D10 = 1.1 mg/kg i.v.) but not that caused by methoxamine (alpha1). It is concluded that B-HT 958 is a partial agonist at peripheral alpha 2-adrenoceptors. In doses of about 1 mg/kg and with low frequency sympathetic stimulation (less than 6.4 Hz) it acts presynaptically as agonist; in this dose the drug acts postsynaptically mainly as antagonist.