B-HT 958--an antagonist at alpha 2-adrenoceptors and an agonist at dopamine autoreceptors in the brain.

B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo[5,4-d]az epine), a compound chemically related to clonidine-like drugs of the azepine type, was described previously as a mixed agonist-antagonist at peripheral alpha 2-adrenoceptor sites. In the present experiments the actions of B-HT 958 on brain noradrenergic and dopaminergic mechanisms were examined using behavioural, pharmacological and biochemical methods. (i) In the dog, intracisternally injected B-HT 958 (300 micrograms/kg) abolished the reflex bradycardia facilitated by the alpha 2-agonist B-HT 920 (10 micrograms/kg i.ci.). (ii) In the whole mouse brain as well as in the rat hypothalamus and neocortex, but not in the hippocampus, amygdala and nucleus accumbens B-HT 958 (5-20 mg/kg s.c.) accelerated the alpha-methyltyrosine (alpha-MT)-induced disappearance of noradrenaline. (iii) B-HT 958 decreased in a dose-dependent manner the exploratory activity of mice (ED50: 6.3 mg/kg s.c.) and slightly enhanced the motor activity of reserpine-treated mice only in high doses. (iv) B-HT 958 (20 mg/kg s.c.) lowered the level of homovanillic acid in the striatum and nucleus accumbens and dose dependently (1-20 mg/kg) slowed the alpha-MT-induced disappearance of dopamine in these 2 brain regions of the rat as well as in the whole mouse brain. (v) The gamma-butyrolactone-induced increase in DOPA levels was effectively antagonized by B-HT 958 (1 and 5 mg/kg s.c.) in the rat striatum and nucleus accumbens. These behavioural, pharmacological and biochemical observations indicate that B-HT 958 possesses central alpha-adrenoceptor blocking activity and exerts a strong agonistic effect on brain dopamine autoreceptors.