Molecular Pharmacology, Vol 12, 854-861, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

The Dopamine-Sensitive Adenylate Cyclase of the Rat Caudate Nucleus

II. A Comparison with the Isoproterenol-Sensitive (Beta) Adenylate Cyclase of the Rat Erythrocyte for Inhibition or Stimulation by Tetrahydroisoquinolines

¹ Department of Cell Biology and Chemical Research Division, Roche Research Center, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110

Tetrahydroisoquinoline (THI) derivatives were tested for agonist and antagonist activity with dopamine and beta adenylate cyclase systems. Agonist activity, seen only with the beta cyclase, was associated with hydroxyl groups at the positions 6 and 7 of the THI moiety, provided that the nitrogen was not methylated and a benzyl group was at position 1 in the S conformation. Methyl, phenyl, or phenethyl substituents at position 1 yielded inactive compounds. The most active derivative was (S)-1-(3,4,5-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, with an EC₅₀ of 0.045 µM. Antagonist activity was detected with both systems and was greater with the S isomer, regardless of the presence of hydroxyl groups on the THI moiety. Methylation of the nitrogen increased the inhibitory potency of the R isomer much more than that of the S conformer. The antagonist activity seen with the beta cyclase was probably responsible for the reduced intrinsic activity of the agonists. It was proposed that agonists of both the phenethylamine and THI types were positioned at the receptor through an interaction of the catecholic ring. While the THI nitrogen was located too far from its binding site, interaction was permitted after the 1-benzyl moiety helped to move the nitrogen binding site closer. The nitrogen of the phenethylamine type of agonist would be free to seek out and contact its binding site. Movement of the receptor would begin, and when the nitrogen was gauche to the catecholic function, as in the THI molecule, activation would occur.