Structure-Activity Relationships in the 8-Amino-6,7,8,9-tetrahydro-3H-benz[e]indole Ring System. Part 2: Effect of 8-Amino Nitrogen Substitution on Serotonin Receptor Binding and Pharmacology
| Autor: | Chiu-Hong Lin, Håkan Wikström, Ennis, Stjernlöf P, Nabil B. Ghazal, Kjell A. Svensson, Robert Louis Hoffman, M. W. Smith, Haadsma-Svensson |
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| Přispěvatelé: | Groningen Research Institute of Pharmacy |
| Rok vydání: | 1995 |
| Předmět: |
Male
Agonist Indoles Intrinsic activity Nitrogen medicine.drug_class Stereochemistry DOPAMINE RECEPTOR Binding Competitive Serotonin Receptor Binding CLONING Rats Sprague-Dawley Structure-Activity Relationship Dopamine Drug Discovery medicine Animals Receptor SITES POTENT Chemistry 8-HYDROXY-2-(DI-NORMAL-PROPYLAMINO)TETRALIN Ligand (biochemistry) Rats AGONIST 5-HT1A RECEPTOR Biochemistry Dopamine receptor Receptors Serotonin RAT Molecular Medicine 5-HT1A receptor SUBTYPE medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry, 38(12), 2217-2230. AMER CHEMICAL SOC |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A series of analogs of the potent and selective 5-HT1A agonist 8-(di-n-propylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (2b) (OSU191) was prepared in which the dipropylamino group was modified to bear a variety of substituents. These compounds were evaluated for both in vitro and in vivo effects, including the establishment of a receptor binding profile for these analogs at the 5-HT1A, dopamine D-2, dopamine D-3, 5-HT1D alpha, and 5-HT1D beta sites. Several of the analogs were evaluated for their biochemical effects in reserpinized rats, specifically with regard to in vivo changes in brain levels of 5-HTP and DOPA. Nearly all of the compounds prepared for this study were exceedingly potent at the 5-HT1A receptor, although most also displayed significant affinity for the dopamine D-2 receptor. A strong preference for the 5-HT1D alpha, over the 5-HT1D beta receptor was also apparent. An analog bearing a butylglutarimide side chain, S-7k, was extremely selective for the 5-HT1A receptor. Although this compound possessed a K-i of 0.6 nM, it elicited only modest changes in 5-HTP brain levels. However, this compound did not appear as an antagonist when tested in a cyclic-AMP-based intrinsic activity assay. |
| Databáze: | OpenAIRE |
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