PHARMACOLOGICAL CHARACTERIZATION OF THE UROSELECTIVE ALPHA-1 ANTAGONIST REC-15 2739 (SB-216469) - ROLE OF THE ALPHA-1L ADRENOCEPTOR IN TISSUE SELECTIVITY .2./

The aim of the present work was to investigate whether or not the uros electivity of Rec 15/2739 and several other alpha-1 adrenoceptor (alph a(1)-AR) antagonists observed in the anesthetized dog could be related to selectivity of these compounds far a particular alpha-1 AR subtype . The binding affinity of the tested compounds for canine prostate alp ha-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 re combinant animal and human alpha-1a, alpha-1b and alpha-1d AR subtypes . Similar results were obtained when the in vivo potency on urethral p ressure was correlated with the affinity for the alpha-1 AR subtypes; also in this case alpha-1L AR gave the best correlation. No correlatio n was obtained by considering the other alpha-1 AR subtypes. The in vi vo hypotensive effects observed in dog after i.v. administration of th e considered compounds correlated only with the binding affinity for t he 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 tis sues of the lower urinary tract of rabbits and dogs are better correla ted with their affinity for the putative alpha-1L subtype than for the alpha-1a subtype. Only the compounds showing selectivity for the alph a-1L subtype versus the alpha-1d subtype proved highly selective in vi vo for the lower urinary tract versus the vascular tissues.