Comparison of the beta-adrenoceptor affinity and selectivity of cetamolol, atenolol, betaxolol, and ICI-118,551.
The objective of the present study was to compare the quantitative differences in the beta 1- vs. beta 2-adrenoceptor affinity and selectivity of cetamolol and its enantiomers to the reference compounds atenolol, betaxolol, and ICI-118,551, using isolated tissues obtained from the dog, guinea pig, and rat. Cetamolol antagonized the beta-adrenoceptor-mediated responses induced by isoproterenol, epinephrine, norepinephrine, and salbutamol, in tissues from both the dog and guinea pig, in a concentration-dependent manner. For a given tissue, the beta-adrenoceptor antagonist activity of cetamolol (measured as a pA2 or pKB value) was independent of the agonist used. In the dog tissues, cetamolol was more potent at inhibiting responses in the coronary artery (beta 1-adrenoceptors) than in the saphenous vein (beta 2-adrenoceptors). In the guinea pig tissues, the potency of cetamolol was approximately the same in the trachea (mixed beta 1- and beta 2-adrenoceptors) and atria (predominately beta 1-adrenoceptors), but lower in the soleus muscle (beta 2-adrenoceptors). Studies with the S-(-) and R-(+) enantiomers of cetamolol demonstrated that the S-(-) enantiomer was approximately 100-fold more potent at beta 1-adrenoceptors than the R-(+) enantiomer. In rat brain, cetamolol displaced [3H]-dihydroalprenolol bound to homogenates of cortex (beta 1-adrenoceptor binding sites) and cerebellum (beta 2-adrenoceptor binding sites). The potency of cetamolol at beta 1-adrenoceptors was found to be similar to that of betaxolol but greater than that of atenolol. However, the magnitude of the beta 1-adrenoceptor selectivity displayed by atenolol and betaxolol was greater than that displayed by cetamolol. In contrast, ICI-118,551 was found to possess potent and selective affinity for beta 2-adrenoceptors.
Rimele
T J
TJ
Department of Pharmacology, Ayerst Laboratories Research, Inc., Princeton, New Jersey 08543-8000.
Henry
D E
DE
Giesa
F R
FR
Buckley
S K
SK
Geiger
G
G
Heaslip
R J
RJ
Lee
D K
DK
Grimes
D
D
D000081:Acetamides / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001262:Atenolol / Q000494:pharmacology*; D015784:Betaxolol; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism
D000081:Acetamides; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; C026777:ICI 118551; D001262:Atenolol; D015784:Betaxolol; D009638:Norepinephrine; C038931:cetamolol