Resolved monophenolic 2-aminotetralins and 1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines: structural and stereochemical considerations for centrally acting pre- and postsynaptic dopamine-receptor agonists

Abstract

A detailed structure-activity relationship is revealed for resolved, centrally acting dopamine (DA) agonists acting on both pre- and postsynaptic DA receptors. The compounds resolved are 5- and 7-hydroxy-2-(di-n-propylamino)tetralin and cis- and trans-7-hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinoline. By the superimposition of the structures of the more active enantiomers of these compounds with those of known dopaminergic agonists, apomorphine and ergolines, a new DA-receptor model is proposed as an outgrowth of current DA-receptor theories. One of the most important concepts of this receptor model is its emphasis on the possible positions taken by the N-substituents of dopaminergic compounds. One of these positions i sterically well defined while the other direction is sterically less critical. The model has been used to explain the lack of dopaminergic activity of some previously reported structures and also to predict properties of novel structures, including inherent chirality, which should be active at DA receptors. Hopefully, this heuristic DA-receptor model will lead to the discovery of more selective and potent pharmacological tools, which ultimately might lead to the development of therapeutic agents for treating diseases of dopaminergic function in the central nervous system.

Locomotor inhibition by the D3 ligand R-(+)-7-OH-DPAT is independent of changes in dopamine release

“…Recently, Daly and Waddington (1993) reported that racemic 7-OH-DPAT induced hypomotility at doses ranging from 35 to 350 nmol/kg s.c. We found that R-(+)-7-OH-DPAT (enantiomeric purity 99.5%, Wikstr6m et al, 1985) induced a biphasic dose response curve in actively exploring rats with hypomotility over a large dose-range (0.1-400nmol/kg s.c., Fig. 1, bottom).…”

Molecular Determinants of Biased Agonism at the Dopamine D2Receptor

“…38 The results showed no preferential activation of either signaling pathways by the propyl-substituted analogues of (R)-4, indicating that the appendage also is a crucial requirement for biased signaling properties (Supporting Information).…”

Computer-Aided Drug Design

“…The recent development of a nonpeptide antagonist of cholecystokinin by Evans et al (87) led to the suggestion that the benzodiazepine ring may exploit some feature common to peptide receptors. Two attempts (88,89) to rationalize dopamine structure-activity relations based on receptor-site models have appeared.…”