Interactions of R(+) and S(-) isomers of befunolol, a partial agonist with high and low affinity sites of beta-adrenoceptors in guinea-pig taenia caecum.
The beta-adrenomimetic and beta-adrenolytic activities of R(+) and S(-) isomers of befunolol, a beta-adrenergic partial agonist, were studied in the guinea-pig taenia caecum. The pA2 value (9.38) of the S(-) isomer against S(-) isoprenaline was significantly different from that (7.94) of the R(+) isomer, while the pD2 values and intrinsic activities of R(+) and S(-) isomers were not significantly different from each other. The competitive inhibition curves of the specific binding of [3H]befunolol (50 nM) to the microsomal fraction from the guinea-pig taenia caecum by S(-) and R(+) isomers were biphasic, suggesting two different affinity binding sites. The affinity ratio of the R(+) isomer against the S(-) isomer to the high affinity site was 0.081 while the affinities of R(+) and S(-) isomers to the low affinity site were not significantly different from each other. The affinity ratio of the R(+) isomer against the S(-) isomer to the high affinity site resembled their potency ratio in beta-adrenergic blocking action. These findings suggest that beta-adrenoceptors contain two different affinity binding sites and that the high affinity binding site for isoprenaline is more stereoselective than the low affinity binding site.
Takayanagi
I
I
Department of Chemical Pharmacology, Toho University School of Pharmaceutical Sciences, Chiba, Japan.
Koike
K
K
Ogishima
M
M
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002432:Cecum / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D011412:Propanolamines / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; C006034:befunolol; D007545:Isoproterenol