Probes for narcotic receptor mediated phenomena. 48. C7- and C8-substituted 5-phenylmorphan opioids from diastereoselective alkylation
| Autor: | Hwan Jung Lim, Richard B. Rothman, Arthur E. Jacobson, Christina M. Dersch, Jeffrey R. Deschamps, Kenner C. Rice |
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| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Alkylation Cyclohexane Stereochemistry Molecular Conformation Substituent Stereoisomerism CHO Cells Crystallography X-Ray Ring (chemistry) Article Structure-Activity Relationship chemistry.chemical_compound Cricetulus Drug Discovery Animals Humans Structure–activity relationship Receptor Cells Cultured Alkyl Pharmacology chemistry.chemical_classification Dose-Response Relationship Drug Organic Chemistry General Medicine Morphinans chemistry Receptors Opioid |
| Zdroj: | European Journal of Medicinal Chemistry. 67:335-343 |
| ISSN: | 0223-5234 |
| Popis: | The exploration of the effect of substituents at C7 and C8 of the 5-phenylmorphans on their affinity for opioid receptors was enabled by our recently introduced “one pot” diastereoselective synthesis that provided C7-oxo, hydroxy and alkyl substituents, C8-alkyl substituted 5-phenylmorphans, and compounds that had a new cyclohexane ring that includes the C7 and C8 carbon atoms of the 5-phenylmorphan. The affinity of the 5-phenylmorphans for opioid receptors is increased by a C8-methyl substituent, compared with its C7 analog. The affinity of the newly synthesized compounds is generally for the μ-opioid receptor, rather than the δ- or κ-receptors. Addition of a new cyclohexane ring to the C7 and C8 positions on the cyclohexane ring of the 5-phenylmorphans enhances μ-receptor affinity, bringing the Ki to the subnanomolar level. Unexpectedly, the N-methyl substituted compounds generally had higher affinity than comparable N-phenethyl-substituted relatives. The configurations of two compounds were determined by single-crystal X-ray crystallographic analyses. |
| Databáze: | OpenAIRE |
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