RT Journal Article
SR Electronic
T1 Dopamine D2 receptor binding sites for agonists. A tetrahedral model.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 391
OP 399
VO 28
IS 5
A1 P Seeman
A1 M Watanabe
A1 D Grigoriadis
A1 J L Tedesco
A1 S R George
A1 U Svensson
A1 J L Nilsson
A1 J L Neumeyer
YR 1985
UL http://molpharm.aspetjournals.org/content/28/5/391.abstract
AB In order to develop a model for the putative binding sites between the D2 dopamine receptor and many of its agonists, we obtained the dissociation constants of many dopaminergic agonists at the high affinity state, D2high, as well as at the low affinity state, D2low, of the receptor. [3H]Spiperone was used to label the D2 dopamine receptors in porcine anterior pituitary tissue. Agonists without any hydroxyl groups, such as 2-aminotetralin, effectively inhibited the binding of [3H]spiperone; the addition of a hydroxyl group corresponding to the "meta" position in dopamine, however, enhanced the potency (in four series of agonists) by an order of magnitude. The R-(-)-enantiomers of the aporphines and 5,6,-dihydroxy-2-dipropylaminotetralin were more potent than the S-(+)-enantiomers. Although the 4-methoxy-2-dipropylaminoindans were potent, the R-(-)-11-methoxyaporphines were not. A tetrahedral model is proposed; this has two sites for agonist attachment, the extremities of the sites being separated by 8 A, and their functional groups directed between 15 degrees and 30 degrees off the orthogonal from the receptor surface. Several steric obstacles are required to account for the inactivity of several congeners.