title: Functional antagonistic activity of Rec 15/2739, a novel alpha-1 antagonist selective for the lower urinary tract, on noradrenaline-induced contraction of human prostate and mesenteric artery.
abstract: The aim of this study was to compare with known reference standards the functional in vitro alpha-1 antagonistic activity of Rec 15/2739 on noradrenaline-induced contractions of human prostate and mesenteric artery. We also characterized these tissues with regard to the alpha-1 adrenoceptor subtypes present. Comparing the apparent pKB values revealed Rec 15/2739 to be one of the most potent compounds action on the prostate. Its potency was slightly lower than that of tamsulosin and was higher than the potencies of prazosin, terazosin and 5-methylurapidil. On the mesenteric artery, tamsulosin was the most potent compound. Comparing the results from the functional studies with those obtained from radioreceptor binding studies, we found that the potency (pKB value) in inhibiting the contraction of prostatic tissue showed a close and significant correlation with the affinity for native and recombinant alpha-1A adrenoceptors. No significant correlation was found with affinity for either the native or the recombinant alpha-1B adrenoceptor subtype, or for recombinant alpha-1d receptors. Similar results were obtained for mesenteric artery. In order to characterize further the alpha-1 adrenoceptor subtypes present in the examined tissues, we investigated the functional effects of chloroethylclonidine, an alpha-1B-D subtypes selective alpha-1 adrenoceptor irreversible antagonist, and those of nifedipine, which antagonizes the extracellular calcium influx primarily mediated by alpha-1A adrenoceptor stimulation. The results indicate the presence of both chloroethylclonidine-sensitive and -insensitive alpha-1 adrenoceptor subtypes in the human prostate, whereas in mesenteric artery the alpha-1A subtype seems to be present exclusively. The possibility that the functionally relevant alpha-1 adrenoceptor subtype could be classified as alpha-1L in both tissues shoul also be considered.
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: C
authors.initials: C
authors.lastname: Taddei
authors.forename: E
authors.initials: E
authors.lastname: Poggesi
authors.forename: P
authors.initials: P
authors.lastname: Angelico
authors.forename: A
authors.initials: A
authors.lastname: Sartani
authors.forename: A
authors.initials: A
authors.lastname: Leonardi
authors.forename: O N
authors.initials: ON
authors.lastname: Gofrit
authors.forename: S
authors.initials: S
authors.lastname: Meretyk
authors.forename: M
authors.initials: M
authors.lastname: Caine
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D002867:Chromones / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D009119:Muscle Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014551:Urinary Tract / Q000187:drug effects*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D002867:Chromones; C099870:Rec 15-2739; D009638:Norepinephrine