INTERACTIONS OF EPINEPHRINE, NOREPINEPHRINE, DOPAMINE AND THEIR CORRESPONDING ALPHA-METHYL-SUBSTITUTED DERIVATIVES WITH ALPHA-ADRENOCEPTORS AND BETA-ADRENOCEPTORS IN THE PITHED RAT

  • 1 January 1984
    • journal article
    • research article
    • Vol. 230  (3) , 595-600
Abstract
The effects of .alpha.-methyl substitution of epinephrine, norepinephrine and dopamine were investigated at .alpha.-1, .alpha.-2, .beta.-1 and .beta.-2 adrenoceptors in the pithed rat. .alpha.-Methyl substitution of these 3 phenethylamines variably altered their capacity to elicit .alpha.-adrenoceptor-mediated vasoconstriction, with slightly enhanced potency being observed for .alpha.-methyl substitution of norepinephrine and dopamine, and a marked reduction in potency for .alpha.-methyl substitution of epinephrine. In all instances, .alpha.-methyl substitution resulted in a higher selectivity for .alpha.-2 adrenoceptors (over .alpha.-1 adrenoceptors). Thus, while epinephrine, norepinephrine and dopamine all produced vasoconstriction that was mediated equally by postsynaptic vascular .alpha.-1 and .alpha.-2 adrenoceptors, their corresponding .alpha.-methyl-substituted derivatives produced vasoconstriction exclusively by activation of postsynaptic vascular .alpha.-2 adrenoceptors. The .beta.-1 adrenoceptor-mediated chronotropic effects of these phenethylamines were inconsistently affected by .alpha.-methyl substitution, with an increase in potency being observed for .alpha.-methyl substitution of norepinephrine and decreases in potency being observed for .alpha.-methyl substitution of epinephrine and dopamine. In marked contrast, .alpha.-methyl substitution of epinephrine, norepinephrine and dopamine was associated with consistent and dramatic increases in potency for .beta.-2 adrenoceptor-mediated vasodepressor activity. .alpha.-2 and .beta.-2 adrenoceptors possess the unique ability to recognize and/or accept .alpha.-methyl substituents on phenethylamines. This ability is not shared by their respective receptor subtypes, the .alpha.-1 and .beta.-1 adrenoceptors. .alpha.-Methylepinephrine is a potent .beta. adrenoceptor agonist, with an apparent 500-fold selectivity for .beta.-2 adrenoceptors over .beta.-1 adrenoceptors.