A-61603, A POTENT ALPHA-1-ADRENERGIC RECEPTOR AGONIST, SELECTIVE FOR THE ALPHA-1A RECEPTOR SUBTYPE

-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrah dronaphthalen-1-yl] methanesulfonamide hydrobromide (A-61603) is a novel and potent alpha -adrenoceptor agonist. In radioligand binding assays, the compound is at least 35-fold more potent at alpha 1A/a receptors than at alpha 1b or alpha 1d sites. In fibroblast cells transfected with alpha 1a recep tors, A-61603 more potently stimulates phosphoinositide hydrolysis tha n norepinephrine, and is antagonized by prazosin. A-61603 is less pote nt in cells transfected with alpha 1b or alpha 1d receptors. A-61603 i s a potent agonist at alpha 1A receptors in rat vas deferens (200- to 300-fold more potent than norepinephrine or phenylephrine, respectivel y) and in isolated canine prostate strips (130- to 165-fold more poten t than norepinephrine or phenylephrine, respectively). In contrast, A- 61603 is only 40-fold more potent than phenylephrine at alpha 1B sites in rat spleen and 35-fold less potent at rat aortic, alpha 1D sites. In an in vivo dog model, A-61603 raises intraurethral prostatic tone t o a greater extent than mean arterial blood pressure. A-61603 induces a presser response in conscious rats at doses 50- to 100-fold lower th an phenylephrine, and the response is not attenuated by pretreatment w ith CEC, whereas YM-617 causes a 100-fold shift in the response. These results indicate that A-61603 is a potent adrenergic agonist, selecti ve for alpha 1A/a receptors, and may prove a useful probe for studies of adrenergic function and alpha 1 adrenoceptor regulation of physiolo gical functions.