Synthesis, Ligand Binding, and Quantitative Structure−Activity Relationship Study of 3β-(4‘-Substituted phenyl)-2β-heterocyclic Tropanes: Evidence for an Electrostatic Interaction at the 2β-Position
| Autor: | Carroll Fi, John W. Boja, Michael J. Kuhar, S. W. Mascarella, Anita H. Lewin, Philip Abraham, Pravin Kotian |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
Models
Molecular Quantitative structure–activity relationship Molecular model Stereochemistry Substituent Nerve Tissue Proteins Ligands Binding Competitive Structure-Activity Relationship chemistry.chemical_compound Cocaine Drug Discovery Animals chemistry.chemical_classification Dopamine Plasma Membrane Transport Proteins Binding Sites Membrane Glycoproteins Bicyclic molecule Membrane Transport Proteins Tropane Ligand (biochemistry) Rats chemistry Heterocyclic compound Molecular Medicine Bioisostere Carrier Proteins |
| Zdroj: | Journal of Medicinal Chemistry. 39:2753-2763 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm960160e |
| Popis: | A set of 3 beta-(4'-substituted phenyl)-2 beta-heterocyclic tropanes was designed, synthesized, and characterized. We discovered that these compounds can function as bioisosteric replacements for the corresponding WIN 35,065-2 analogs which possess a 2 beta-carbomethoxy group. Several of the compounds showed high affinity and selectivity for the dopamine transporter (DAT) relative to the serotonin and norepinephrine transporters. From the structure-activity relationship study, the 3 beta-(4'-chlorophenyl)-2 beta-(3'-phenylisoxazol-5-yl)tropane (5d) emerged as the most potent and selective compound. The binding data for 2 beta-heterocyclic tropanes were found to show a high correlation with molecular electrostatic potential (MEP) minima near one of the heteroatoms in the 2 beta-substituents. In contrast, low correlations were found for other MEP minima near the 2 beta-substituent as well as for calculated log P or substituent volume. These quantitative structure-activity relationship studies are consistent with an electrostatic contribution to the binding potency of these WIN 35,065-2 analogs at the DAT. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|