Further characterization of structural requirements for agonists at the striatal dopamine D2 receptor and a comparison with those at the striatal dopamine D1 receptor. Studies with a series of monohydroxyaminotetralins on acetylcholine release from rat striatum

MP Seiler and R Markstein

A series of phenolic hydroxy-2-aminotetralins with either a primary or a tertiary (N,N-di-n-propylated) amino group was investigated on electrically evoked acetylcholine release from striatal slices of reserpinized rats, a dopamine (DA) D2 receptor model. 7-Hydroxy-2- aminotetralin (7-OH-AT) was found to be the most active inhibitor among the primary amines, whereas 5-hydroxy-2-(N,N-dipropylamino)tetralin (5- OH-DPAT) was the most potent compound among the tertiary amines; in the 7-OH series, the activity resided in the (2R)-enantiomers, in contrast to the 5-OH series, where the (2S)-enantiomers represented the effective form. A similar structure-activity pattern was earlier found for the same series of DA agonists at the striatal DA D1 receptor. Differences between the effects of the compounds at the two DA receptor subtypes concerned the N,N-dipropyl substitution which influenced the D2 activity much more pronouncedly, and an added 6-OH group (i.e., a catechol function), which seemed to be of foremost importance at the D1 site. These results suggest two similar major binding sites for the DA receptor subtypes, but differences with respect to additional binding sites. According to this model, DA would interact with both DA receptor subtypes in the beta-rotamer conformation; however, N,N-dipropylation similarly should cause a change in preferred conformation toward the alpha-rotamer form. The potency with respect to acetylcholine release correlated with [3H] spiroperidol binding, but not with [3H]DA binding, confirming that the former binding involves the active site of the D2 receptor.

Volume 26, Issue 3, pp. 452-457, 11/01/1984
Copyright © 1984 by American Society for Pharmacology and Experimental Therapeutics