Bridged gamma-carbolines and derivatives possessing selective and combined affinity for 5-HT2 and D2 receptors
| Autor: | R E, Mewshaw, L S, Silverman, R M, Mathew, C, Kaiser, R G, Sherrill, M, Cheng, C W, Tiffany, E W, Karbon, M A, Bailey, S A, Borosky |
|---|---|
| Rok vydání: | 1993 |
| Předmět: |
Indole test
Bridged-Ring Compounds Male Ketanserin Binding Sites Stereochemistry Receptors Dopamine D2 Benzisoxazole Alkylation chemistry.chemical_compound Mice Structure-Activity Relationship chemistry Receptors Serotonin Drug Discovery medicine Molecular Medicine Moiety Animals Serotonin Receptor Lead compound medicine.drug Carbolines |
| Zdroj: | Journal of medicinal chemistry. 36(10) |
| ISSN: | 0022-2623 |
| Popis: | A series of 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles and 6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indoles was prepared. Structural modifications of the lead compound, 11-[4-(4-fluorobenzoyl)propyl]-5,6,7,8,9,10-hexahydro-7,10- iminocyclohept[b]indole (5, Ki = 0.82 nM vs [3H]ketanserin) enabled the identification of the functionality necessary for high affinity at serotonin 5-HT2 and dopamine D2 receptors in ligand binding studies. The indole ring, as well as the benzoyl or isosteric benzisoxazole moiety, were essential for high affinity. Variations of the length of the side chains resulted in ligands having either selective affinity for the 5-HT2 receptor or a combination of 5-HT2 and D2 affinity. In vivo binding studies were performed on selected members in this series. The most potent member, 2-fluoro-11-[4-(4-fluorobenzoyl)butyl]-5,6,7,8,9,10-hexahydro-7,10- iminocyclohept[b]indole (36) had an ED50 of < 1 mg/kg at the 5-HT2 and D2 receptors following oral administration. |
| Databáze: | OpenAIRE |
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