Prolactin-Suppressive Effects of Two Aminotetralin Analogs of Dopamine: Their Use in the Characterization of the Pituitary Dopamine Receptor*

Abstract

To characterize the conformational requirements of the anterior pituitary dopamine (DA) receptor, we have examined the PRL-suppressive effects of two semirigid DA agonists of the 2-aminotetralin series: 2-amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-5.6-DTN), an a-rotamer, and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-6,7-DTN), the corresponding β-rotamer. In vivo studies were conducted on conscious, estrogen-primed male rats bearing indwelling right atrial catheters; in vitro studies utilized isolated rat anterior pituitary cells in 4-day primary culture. Both compounds exhibited full agonist activity in both systems, as judged by dose-response curves parallel to that of DA and identical maximal PRL suppression. In vivo A-5,6-DTN was equipotent to DA, and A-6,7-DTN was 8 times as potent as DA. The effects of all three agonists were unaltered by phentolamine or propranolol and were attenuated to a similar extent by haloperidol. The in vitro potency ratios were A-6,7-DTN:DA:A-5,6-DTN = 13.2:1:0.085. The reduced in vitro potency of the α-rotamer suggested that pharmacokinetic differences had contributed to the in vivo findings. The effects of all three agonists were completely blocked by haloperidol and were attenuated by high concentrations of phentolamine and propranolol; the latter effect has been attributed to nonspecific dopaminergic suppression. Results obtained with a series of other agonists and antagonists suggested that only specific DA receptor mediation is of importance in the PRL-suppressive action of the 2-aminotetralin analogs of DA. The DA agonists, apomorphine, bromocryptine, and piribidil, which have little or no activity in the vascular DA receptor model, exhibited strong dopaminergic activity in vitro. Dibutyryl cAMP, theophylline, and isobutylmethylxanthine stimulated PRL release in vitro. The present results differ from those in the renovascular and striatal adenylate cyclase DA receptor models and appear independent of adenylate cyclase mediation. It is suggested that the β-rotameric form is the preferred conformation for activation of the anterior pituitary DA receptor.