Abstract
SK&F 104856 (2-vinyl-7-chloro-3,4,5,6-tetrahydro-4-methyl-thieno[4,3,2ef][3] benzazepine) shows a similar selectivity profile to the previously reported alpha adrenoceptor antagonist, SK&F 104078 (6-chloro-9-[(3-methyl-2-butenyl)oxy]-3-methyl-1H-2,3,4,5-tetrahydro-3- benzazepine), having the ability to block alpha-1 and postjunctional alpha-2 adrenoceptors, although having little or no activity at most prejunctional alpha-2 adrenoceptors. SK&F 104856 is more potent than SK&F 104078, and lacks the 5-hydroxytryptamine receptor antagonist activity associated with the earlier compound. The postjunctional vs. prejunctional selectivity of SK&F 104856 at alpha-2 adrenoceptors in the same tissue preparation was demonstrated in both canine and human saphenous vein. Concentrations substantially higher than those required to block postjunctional alpha-2 adrenoceptor-agonist induced vasoconstriction had no effect on the ability of norepinephrine, acting on prejunctional alpha-2 adrenoceptors, to inhibit stimulation evoked transmitter overflow in the human tissue, and only a small effect in the canine vein. As observed with SK&F 104078, SK&F 104856 has some prejunctional alpha-2 adrenoceptor antagonist activity in the rat vas deferens, although the receptor dissociation constant is nearly 50-fold higher than that at the postjunctional alpha-2 adrenoceptor in the canine saphenous vein. The results obtained with SK&F 104856 provide additional evidence to support the premise that alpha-2 adrenoceptors can be functionally differentiated. Because SK&F 104856 can selectively antagonize certain alpha-2 adrenoceptor-mediated responses, this agent may be a useful tool to evaluate the functional roles of the multiple alpha-2 adrenoceptor subtypes that have been identified in biochemical and molecular studies.
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|