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 (α1-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 thealpha-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 andalpha-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 otheralpha-1 AR subtypes. The in vivohypotensive 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 thealpha-1a subtype. Only the compounds showing selectivity for the alpha-1L subtype versus thealpha-1d subtype proved highly selective in vivo for the lower urinary tract versus the vascular tissues.
Footnotes
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Send reprint requests to: Rodolfo Testa, Pharmaceutical R&D Division, Recordati S.p.A., Via Civitali 1, 20148, Milano, Italy.
- Abbreviations:
- α1-AR
- α1-adrenoceptor
- BPH
- benign prostatic hyperplasia
- NE
- norepinephrine
- UP
- urethral pressure
- DBP
- diastolic blood pressure
- CEC
- chloroethylclonidine
- CHO cells
- Chinese hamster ovary cells
- Received April 29, 1996.
- Accepted February 5, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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