Correlation of alpha- and beta-rotameric forms of 2-substituted octahydrobenzo[f]quinoline dopamine congeners with high and low affinity states of the anterior pituitary dopamine receptor and prolactin inhibition

PR Findell, SM Torkelson, JC Craig and RI Weiner

Reproductive Endocrinology Center, University of California, San Francisco 94143.

The flexible dopamine (DA) molecule exists in one or the other of its two conformational extremes (alpha- or beta-rotamer) and its receptor in the anterior pituitary gland exists in a high and a low affinity state. A series of novel, rigid DA congeners (2-substituted octahydrobenzo[f]quinolines) was synthesized and used to investigate the conformation of DA preferred by its anterior pituitary receptor and the significance of recognition of the two affinity states to the inhibition of prolactin (PRL) secretion. Analysis of competition curves of congeners for [3H]spiperone binding to bovine anterior pituitary membranes was used to calculate affinity constants. Congeners in the beta-rotamer conformation showed a biphasic competition curve as observed for DA. The curves were resolved into high (nM) and low (microM) affinity binding sites. This biphasic binding could be converted to monophasic low affinity binding in the presence of a nonhydrolyzable GTP analog. The congeners in the alpha-rotameric conformation showed monophasic low affinity binding. The potency of congeners to suppress PRL release was evaluated in cell cultures of dispersed bovine anterior pituitary. Congeners recognizing the high affinity binding site were 100-fold more potent in suppressing PRL release than those recognizing only low affinity binding sites. Dihydroxy congeners versus monohydroxy congeners and cyanomethyl group substituted versus methylthiomethyl substituted congeners occupied greater proportions of high affinity binding sites. Increasing proportions of high affinity sites occupied increased the potency of the congener to suppress PRL release. These results suggest that the beta-rotameric conformational extreme of DA is preferred by its receptor in the anterior pituitary gland and that the high affinity state of this receptor is functionally important in mediating the inhibition of PRL secretion.

Volume 33, Issue 1, pp. 78-83, 01/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics