A stereochemical and conformational model of dopaminergic agonist and antagonist activity: further evaluation.
Conformational energy calculations using the Molecular Mechanics II (MM2) program have been performed on 2-aminotetrahydronaphthalene (ATN) and 2-aminoindan derivatives which are active or inactive at dopamine receptors. The results were used to test a stereochemical and conformational model previously proposed for dopaminergic activity. The conformer predicted to be optimal for agonist activity was found to have relatively low energy (less than 1.5 kcal/mol) for all of the agonists examined. The model successfully: (1) explained the relative activity or inactivity of compounds such as cis- and trans-1-methyl-5-hydroxyl ATN derivatives and the corresponding cis- and trans-octohydrobenzo[f]quinolines; (2) predicted the more potent antipode of 2-aminoindan dopaminergic agonists; and (3) explained the structure--activity peculiarities of 3-(3-hydroxyphenyl)-N-alkylpiperidines in which the potency is increased for (3S)-isomers and decreased for (3R)-isomers when the N-alkyl group is greater than propyl. Predictions of postsynaptic dopaminergic antagonism were also made for some of the compounds. In agreement with previous conclusions, the inactivity of ATN derivatives with a 2-methyl or 5-propyl group was attributed to steric interference at the receptor since those groups did not have a significant conformational effect on the receptor ligand.
Froimowitz
M
M
Alcohol and Drug Abuse Research Center, Belmont.
Baldessarini
R J
RJ
D008956:Models, Chemical; D008968:Molecular Conformation; D009281:Naphthalenes / Q000494:pharmacology*; D011954:Receptors, Dopamine / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013816:Thermodynamics
D009281:Naphthalenes; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; C006561:2-aminotetralin