In vivo pharmacological profile of SL 84.0418, a new selective, peripherally active alpha 2-adrenoceptor antagonist

SL 84.0418 is a novel pyrrolo-indole derivative with potent and selective alpha 2-adrenoceptor antagonist activity in vitro and anti-hyperglycemic properties in vivo. In the present study we demonstrated that SL 84.0418 and its active (+) enantiomer, SL 86.0715, show a high degree of selectivity for alpha 2-adrenoceptors in vivo, preferentially blocking alpha 2-adrenoceptors in the periphery. While having no effects on basal blood pressure and heart rate, p.o. (3 and 10 mg/kg) or i.v. (0.3 mg/kg) administered SL 84.0418 or SL 86.0715 antagonized the hypertensive responses mediated by postsynaptic vascular alpha 2-adrenoceptors after the administration of UK 14304 or norepinephrine to pithed rats. The (-) enantiomer of SL 84.0418, SL 86.0714, was devoid of alpha 2-adrenoceptor antagonist properties in vivo, while the (+) enantiomer of SL 84.0418, SL 86.0715, showed alpha 2-adrenoceptor antagonist activity similar to that of the racemate. SL 84.0418 (3 mg/kg p.o.) did not modify the centrally mediated hypotensive and bradycardic effects of i.c.v. administered clonidine. Furthermore, in the mouse, SL 84.0418 potently antagonized the hyperglycemic responses to epinephrine or UK 14304, which are mediated by peripheral alpha 2-adrenoceptors, but failed (in doses up to 30 mg/kg i.p.) to antagonize the clonidine-induced hypolocomotion, which is mediated by central alpha 2-adrenoceptors. These results suggest that SL 84.0418 preferentially antagonizes peripheral alpha 2-adrenoceptors. SL 84.0418 administered to pithed rats (3 mg/kg p.o. or 0.3 mg/kg i.v.) did not modify the vasoconstriction induced by cirazoline (effect mediated by alpha 1-adrenoceptors) nor the tachycardia induced by norepinephrine (effect mediated by beta-adrenoceptors).(ABSTRACT TRUNCATED AT 250 WORDS)