Molecular Pharmacology, Vol 10, 721-726, Copyright © 1974 by the American Society for Pharmacology and Experimental Therapeutics

The Dopamine-Sensitive Adenylate Cyclase of Rat Caudate Nucleus

I. Comparison with the Isoproterenol-Sensitive Adenylate Cyclase (Beta Receptor System) of Rat Erythrocytes in Responses to Dopamine Derivatives

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

Various analogues of dopamine were examined for agonist activity with respect to the dopamine-sensitive adenylate cyclase of rat caudate nucleus and the isoproterenol-sensitive enzyme of rat erythrocytes. In both systems decreased activity was associated with 5-methyl, 6-methyl, 2-phenyl, or (R, -)--methyl substitution. With the dopamine-sensitive cyclase system N-alkyl, (S, +)--methyl, and (R, -)--hydroxy substitution resulted in decreased activity, in contrast to results with the isoproterenol-sensitive cyclase. The isomers of the tetrahydroisoquinolines, salsolinol and its N-methylated derivatives, were inactive, lending support to the concept that the nitrogen and catechol moieties were in a trans rather than a gauche conformation. It is suggested that the receptors for the dopamine- and isoproterenol-sensitive adenylate cyclases could have identical primary structures but that they are folded in the membrane in such a way that the binding sites for the active groups of the agonists differ in their relative positions.

Note:
ACKNOWLEDGMENT The authors wish to acknowledge the assistance of Dr. S. Teitel, Chemical Research Division, in developing the concepts involving stereochemistry.

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