title: Pharmacological characterization of the uroselective alpha-1 antagonist Rec 15/2739 (SB 216469): role of the alpha-1L adrenoceptor in tissue selectivity, part II.
abstract: The aim of the present work was to investigate whether or not the uroselectivity of Rec 15/2739 and several other alpha-1 adrenoceptor (alpha1-AR) antagonists observed in the anesthetized dog could be related to selectivity of these compounds for a particular alpha-1 AR subtype. The binding affinity of the tested compounds for canine prostate alpha-1 ARs and their in vitro functional affinity for the alpha-1 ARs of rabbit urethra and prostate correlated with their functional affinity for the alpha-1L AR subtype, but not with the binding affinity for recombinant animal and human alpha-1a, alpha-1b and alpha-1d AR subtypes. Similar results were obtained when the in vivo potency on urethral pressure was correlated with the affinity for the alpha-1 AR subtypes; also in this case alpha-1L AR gave the best correlation. No correlation was obtained by considering the other alpha-1 AR subtypes. The in vivo hypotensive effects observed in dog after i.v. administration of the considered compounds correlated only with the binding affinity for the animal and human alpha-1d subtype. In conclusion, the results shown in the present paper indicate that the potencies of different alpha-1 antagonists against the contractions induced by norepinephrine on tissues of the lower urinary tract of rabbits and dogs are better correlated with their affinity for the putative alpha-1L subtype than for the alpha-1a subtype. Only the compounds showing selectivity for the alpha-1L subtype versus the alpha-1d subtype proved highly selective in vivo for the lower urinary tract versus the vascular tissues.
authors.affiliation: Pharmaceutical R&D Division, Recordati S.p.A., Milano, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Testa
authors.forename: L
authors.initials: L
authors.lastname: Guarneri
authors.forename: P
authors.initials: P
authors.lastname: Angelico
authors.forename: E
authors.initials: E
authors.lastname: Poggesi
authors.forename: C
authors.initials: C
authors.lastname: Taddei
authors.forename: G
authors.initials: G
authors.lastname: Sironi
authors.forename: D
authors.initials: D
authors.lastname: Colombo
authors.forename: A C
authors.initials: AC
authors.lastname: Sulpizio
authors.forename: D P
authors.initials: DP
authors.lastname: Naselsky
authors.forename: J P
authors.initials: JP
authors.lastname: Hieble
authors.forename: A
authors.initials: A
authors.lastname: Leonardi
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D002867:Chromones / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D008297:Male; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014551:Urinary Tract / Q000187:drug effects*
chemical_list: D000317:Adrenergic alpha-Antagonists; D002867:Chromones; C099870:Rec 15-2739