R1-adrenoreceptor (AR) subtypes and 5-HT1A serotoninergic receptors was assessed by binding assays in Chinese hamster ovary and HeLa cell membranes expressing the human cloned receptors. Moreover, their receptor selectivity was further determined in functional experiments in isolated rat prostate (R1A), vas deferens (R1A), aorta (R1D), and spleen (R1B). In functional assays, compound 5 was the most potent at R1D-ARs with a reversed selectivity profile (R1D > R1A > R1B) relative to both prototype 1 and phendioxan (2) (R1A > R1D > R1B), whereas compound 8, bearing a carbonyl moiety at position 1, was the most potent at R1A-ARs with a selectivity profile similar to that of prototypes. The least potent of the series was the trans isomer 6, suggesting that optimum R1-AR blocking activity in this series is associated with a cis relationship between the 2-side chain and the 4-phenyl ring rather than a trans relationship as previously observed for the 2-side chain and the 3-phenyl ring in 2 and related compounds. Binding affinity results were not in complete agreement with the selectivity profiles deriving from functional experiments. Although a firm explanation was not available, neutral and negative antagonism and receptor dimerization were considered as two possibilities to account for the difference between binding and functional affinities. Finally, compound 5 was selected for a modeling study in comparison with 1, mephendioxan (3), and open phendioxan (4) to achieve information on the physicochemical interactions that account for its high affinity toward R1d/D-ARs.
|Titolo:||Structure-activity relationships in 1,4-benzodioxan-related compounds. 7. Selectivity of 4-phenylchroman analogues for alpha(1)-adrenoreceptor subtypes|
|Autori interni:||QUAGLIA, Wilma|
|Data di pubblicazione:||2002|
|Rivista:||JOURNAL OF MEDICINAL CHEMISTRY|
|Appare nelle tipologie:||Articolo|