N,N-Diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide: a novel, exceptionally selective, potent delta opioid receptor agonist with oral bioavailability and its analogues
| Autor: | William Brown, Claude Godbout, Denis Projean, Bryan K. Takasaki, Ralf Schmidt, Joanne Butterworth, Wei Zhongyong, Helene Gagnon, Lars Gawell, Pierre-Emmanuel Morin, Chris Walpole, Daniel Delorme, Hua Yang, Julie Ducharme, Edward Roberts, Paul Jones, Maryse Labarre, Shi-Yi Yue, Andrea Jakob, Augustus Kamassah, Kemal Payza, Niklas Plobeck, Fei Zhou, Stephane St-Onge |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Agonist
Models Molecular medicine.drug_class Stereochemistry Receptors Opioid mu Administration Oral Biological Availability In Vitro Techniques Transfection Chemical synthesis κ-opioid receptor Mass Spectrometry Piperazines Cell Line δ-opioid receptor chemistry.chemical_compound Radioligand Assay Structure-Activity Relationship Piperidines Receptors Opioid delta Drug Discovery medicine Animals Humans Benzamide Receptor Chromatography High Pressure Liquid Receptors Opioid kappa Stereoisomerism Rats Piperazine chemistry Benzamides Microsomes Liver Molecular Medicine Thermodynamics μ-opioid receptor |
| Zdroj: | Journal of medicinal chemistry. 43(21) |
| ISSN: | 0022-2623 |
| Popis: | The design, synthesis, and pharmacological evaluation of a novel class of delta opioid receptor agonists, N, N-diethyl-4-(phenylpiperidin-4-ylidenemethyl)benzamide (6a) and its analogues, are described. These compounds, formally derived from SNC-80 (2) by replacing the piperazine ring with a piperidine ring containing an exocyclic carbon carbon double bond, were found to bind with high affinity and exhibit excellent selectivity for the delta opioid receptor as full agonists. 6a, the simplest structure in the class, exhibited an IC(50) = 0.87 nM for the delta opioid receptors and extremely high selectivity over the mu receptors (mu/delta = 4370) and the kappa receptors (kappa/delta = 8590). Rat liver microsome studies on a selected number of compounds show these olefinic piperidine compounds (6) to be considerably more stable than SNC-80. This novel series of compounds appear to interact with delta opioid receptors in a similar way to SNC-80 since they demonstrate similar SAR. Two general approaches have been established for the synthesis of these compounds, based on dehydration of benzhydryl alcohols (7) and Suzuki coupling reactions of vinyl bromide (8), and are herewith reported. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|