Pharmacological evaluation of the beta-adrenoceptor agonist properties of N-benzyl substituted trimetoquinol analogues.
The beta 1- and beta 2-adrenoceptor agonist properties of trimetoquinol (TMQ, I) and N-benzyl ring substituted TMQ analogues (II, 4'-methylbenzylTMQ; III, 4'-chloro-benzylTMQ; IV, 4'-methoxybenzylTMQ; V, 4'-nitrobenzylTMQ; VI, 3',4'-dichlorobenzylTMQ; and VII, 4'-aminobenzylTMQ) were studied in guinea pig atria and trachea. All compounds gave concentration-dependent responses in atria and trachea, and the rank order of beta-adrenoceptor agonist potency was I greater than VII greater than II greater than V greater than IV greater than VI greater than III and I greater than VII greater than IV = VI greater than V greater than III greater than II, respectively. Whereas the N-benzyl substitution reduced potency for beta-agonist activity, the beta 2/beta 1-selectivity ratio was enhanced by addition of groups to the N-benzyl ring, and the rank order of beta 2-selectivity was VI (10-fold) greater than III (8-fold) = IV (8-fold) greater than VII (3-fold) greater than V = I greater than II. The results show that varying the nature of substituents on the N-benzyl ring of TMQ produces compounds which retain greater beta 2-selectivity.
Shams
G
G
Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus 43210.
Harrold
M W
MW
Grazyl
B
B
Miller
D D
DD
Feller
D R
DR
D000318:Adrenergic beta-Agonists; D000818:Animals; D001593:Benzyl Compounds / Q000494:pharmacology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D009126:Muscle Relaxation / Q000187:drug effects; D014132:Trachea / Q000187:drug effects; D014213:Tretoquinol / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D001593:Benzyl Compounds; D014213:Tretoquinol