Molecular Pharmacology, Vol 10, 605-614, Copyright © 1974 by the American Society for Pharmacology and Experimental Therapeutics

Structure-Activity Relationships of Adrenergic Compounds on the Adenylate Cyclase of Frog Erythrocytes

¹ Departments of Pharmacology and Medicine and Department of Molecular Biology, Division of Biology, Albert Einstein College of Medicine, Bronx, New York 10461

Frog erythrocyte adenylate cyclase possesses characteristics of a beta-2 adrenergic receptor; this enzyme was used to test various adrenergic compounds for their effects on cyclic 3', 5'-AMP formation. Agonists demonstrate different EC₅₀ values and intrinsic activities. A large amino substituent and a hydroxyl group in the levo configuration at the -carbon increase the potency of agonists and antagonists, but neither modification is essential for activity. Compounds containing a methyl group at the -position with the erythro configuration retain their agonist or antagonist activities. Agonists must have two functional groups on the phenyl ring; a functional group other than hydroxyl can be substituted only at position 3. The effect of ring substitution on the activity of an antagonist depends on the nature of the adjacent functional group. Studies with trimethoquinol suggest correlation of the observed EC₅₀ with affinity. There is an excellent correlation between activation of frog erythrocyte adenylate cyclase by the agonists studied and the physiological responses in mammalian preparations.

Note:
ACKNOWLEDGMENTS The authors thank Dr. W. T. Comer of Mead Johnson for generously supplying many of the compounds used in this study and for several helpful discussions. We are grateful to Drs. C. F. Brewer and M. H. Makman for critically reviewing this manuscript.