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The dopamine sensitive adenylate cyclase of the rat caudate nucleus part 2 a comparison with the isoproterenol sensitive beta adenylate cyclase of the rat erythrocyte for inhibition or stimulation by tetra hydro iso quinolines


Molecular Pharmacology 12(5): 854-861
The dopamine sensitive adenylate cyclase of the rat caudate nucleus part 2 a comparison with the isoproterenol sensitive beta adenylate cyclase of the rat erythrocyte for inhibition or stimulation by tetra hydro iso quinolines
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 N 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 [median effective concentration] of 0.045 .mu.M. 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 N 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. Agonists of both the phenethylamine and THI types were probably positioned at the receptor through an interaction of the catecholic ring. While the THI N was located too far from its binding site, interaction was permitted after the 1-benzyl moiety helped to move the N binding site closer. The N 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 N was guache to the catecholic function, as in the THI molecule, activation would occur.

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Accession: 006632793



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