Vol. 281, Issue 3, 1284-1293, 1997

Pharmacological Characterization of the Uroselective Alpha-1 Antagonist Rec 15/2739 (SB 216469): Role of the Alpha-1L Adrenoceptor in Tissue Selectivity, Part II

R. Testa, L. Guarneri, P. Angelico, E. Poggesi, C. Taddei, G. Sironi, D. Colombo, A. C. Sulpizio, D. P. Naselsky, J. P. Hieble and A. Leonardi

Pharmaceutical R&D Division, Recordati S.p.A., 20148 Milano, Italy (R.T., L.G., P.A., E.P., C.T., G.S., D.C., A.L.) and Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania (A.C.S., D.P.N., J.P.H.)

The aim of the present work was to investigate whether or not the uroselectivity of Rec 15/2739 and several other alpha-1 adrenoceptor (₁-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.