title: Interactions of epinephrine, norepinephrine, dopamine and their corresponding alpha-methyl-substituted derivatives with alpha and beta adrenoceptors in the pithed rat.
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 three 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. However, 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. These results indicate that alpha-2 and beta-2 adrenoceptors possess the unique ability to recognize and/or accept alpha-methyl substituents on phenethylamines and that this ability is not shared by their respective receptor subtypes, the alpha-1 and beta-1 adrenoceptors. Furthermore, the results show that alpha-methylepinephrine is a potent beta adrenoceptor agonist, with an apparent 500-fold selectivity for beta-2 adrenoceptors over beta-1 adrenoceptors.
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D003655:Decerebrate State; D003846:Deoxyepinephrine / Q000031:analogs & derivatives / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000031:analogs & derivatives / Q000378:metabolism*; D008297:Male; D008771:Nordefrin / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D010643:Phenoxybenzamine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011941:Receptors, Adrenergic / Q000378:metabolism*; D012110:Reserpine / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D011941:Receptors, Adrenergic; D010643:Phenoxybenzamine; C029205:alpha-methylepinephrine; D015016:Yohimbine; C023492:alpha-methyldopamine; D012110:Reserpine; D011433:Propranolol; D003846:Deoxyepinephrine; D008771:Nordefrin; D004298:Dopamine; D009638:Norepinephrine; D011224:Prazosin; D004837:Epinephrine