Pharmacological characterization of the uroselective alpha-1 antagonist Rec 15/2739 (SB 216469): role of the alpha-1L adrenoceptor in tissue selectivity, part II.
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.
Testa
R
R
Pharmaceutical R&D Division, Recordati S.p.A., Milano, Italy.
Guarneri
L
L
Angelico
P
P
Poggesi
E
E
Taddei
C
C
Sironi
G
G
Colombo
D
D
Sulpizio
A C
AC
Naselsky
D P
DP
Hieble
J P
JP
Leonardi
A
A
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*
D000317:Adrenergic alpha-Antagonists; D002867:Chromones; C099870:Rec 15-2739