This proposal is a study of typical and atypical dopamine agonists and antagonists with a particular emphasis on antipsychotic drugs. One aspect is a study of the molecular features and three-dimensional structures that are associated with atypical and/or selective action at dopamine receptors. The biologically active conformers of the compounds will be determined using MM2 and AMBER energy minimization calculations. Solvent effects will eventually be simulated with Monte Carlo and molecular dynamics techniques. The geometries of low energy conformers will be quantitatively superimposed for structurally related compounds and across classes of compounds with similar pharmacological properties. A second aspect of this proposal is the synthesis of derivatives of octohydrobenzo (f) quinolines. The expectation is that one enantiomer of these compounds will be a superpotent dopamine agonist whereas the other enantiomer will be an antagonist of a new structural type. A third aspect of the proposal is the pharmacological testing of the compounds using in vitro assays such as radioligand binding assays selective for receptor subtypes and adenylate cyclase assays. The long-term objective of this work is to determine the three-dimensional molecular structures that dopaminergic compounds share and that can account for their typical/atypical and selective/nonselective pharmacological properties. It may be possible to break more complex pharmacological properties into simpler components. A number of hypotheses will be tested as to the molecular features associated with certain kinds of agonism or antagonism. With the achievement of this knowledge, it may become possible to design novel dopamine agonists and antagonists with more selective clinical actions and fewer undesirable side effects.
|Froimowitz, M; Deng, Y; Jacob, J N et al. (1995) Dopaminergic (4aR,10bS)-cis- and (4aS,10bS)-trans-octahydrobenzo[F]quinolines have similar pharmacophores. Drug Des Discov 13:73-81|
|Froimowitz, M; Patrick, K S; Cody, V (1995) Conformational analysis of methylphenidate and its structural relationship to other dopamine reuptake blockers such as CFT. Pharm Res 12:1430-4|
|Teeter, M M; Froimowitz, M; Stec, B et al. (1994) Homology modeling of the dopamine D2 receptor and its testing by docking of agonists and tricyclic antagonists. J Med Chem 37:2874-88|
|Froimowitz, M; Cody, V (1993) Biologically active conformers of phenothiazines and thioxanthenes. Further evidence for a ligand model of dopamine D2 receptor antagonists. J Med Chem 36:2219-27|
|Froimowitz, M; Ramsby, S (1991) Conformational properties of semirigid antipsychotic drugs: the pharmacophore for dopamine D-2 antagonist activity. J Med Chem 34:1707-14|