title: A-61603, a potent alpha 1-adrenergic receptor agonist, selective for the alpha 1A receptor subtype.
abstract: N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydro naphthalen-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 receptors, A-61603 more potently stimulates phosphoinositide hydrolysis than norepinephrine, and is antagonized by prazosin. A-61603 is less potent in cells transfected with alpha 1b or alpha 1d receptors. A-61603 is a potent agonist at alpha 1A receptors in rat vas deferens (200- to 300-fold more potent than norepinephrine or phenylephrine, respectively) and in isolated canine prostate strips (130- to 165-fold more potent 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 to a greater extent than mean arterial blood pressure. A-61603 induces a pressor response in conscious rats at doses 50- to 100-fold lower than phenylephrine, and the response is not attenuated by pretreatment with CEC, whereas YM-617 causes a 100-fold shift in the response. These results indicate that A-61603 is a potent adrenergic agonist, selective for alpha 1A/a receptors, and may prove a useful probe for studies of adrenergic function and alpha 1 adrenoceptor regulation of physiological functions.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, Illinois, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Knepper
authors.forename: S A
authors.initials: SA
authors.lastname: Buckner
authors.forename: M E
authors.initials: ME
authors.lastname: Brune
authors.forename: J F
authors.initials: JF
authors.lastname: DeBernardis
authors.forename: M D
authors.initials: MD
authors.lastname: Meyer
authors.forename: A A
authors.initials: AA
authors.lastname: Hancock
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002417:Cattle; D002460:Cell Line; D004285:Dogs; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism
chemical_list: C094643:A 61603; D058646:Adrenergic alpha-1 Receptor Agonists; D007093:Imidazoles; D018340:Receptors, Adrenergic, alpha-1; D013764:Tetrahydronaphthalenes