Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists
| Autor: | Simon M. Bushell, Ming-Jung Wu, George Hynd, Dow P. Hurst, Billy R. Martin, Dana E. Selley, Gulay Zengin, Jianzhong Lu, Patricia H. Reggio, Cindy Tartal, John W. Huffman, Jenny L. Wiley, Kristen Bushell, Alicia L. S. Thompson, Michael P. Cassidy |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Agonist
Models Molecular Cannabinoid receptor Indoles Magnetic Resonance Spectroscopy Alkylation medicine.drug_class Stereochemistry medicine.medical_treatment Clinical Biochemistry Pharmaceutical Science CHO Cells Biochemistry Partial agonist Binding Competitive Mass Spectrometry Receptor Cannabinoid CB2 Structure-Activity Relationship Receptor Cannabinoid CB1 Cricetinae Drug Discovery medicine Animals Receptor Molecular Biology Indole test Chemistry Organic Chemistry JWH-018 Docking (molecular) Guanosine 5'-O-(3-Thiotriphosphate) Molecular Medicine Cannabinoid medicine.drug |
| Zdroj: | Bioorganicmedicinal chemistry. 13(1) |
| ISSN: | 0968-0896 |
| Popis: | In an effort to improve indole-based CB(2) cannabinoid receptor ligands and also to develop SAR for both the CB(1) and CB(2) receptors, 47 indole derivatives were prepared and their CB(1) and CB(2) receptor affinities were determined. The indole derivatives include 1-propyl- and 1-pentyl-3-(1-naphthoyl)indoles both with and without a 2-methyl substituent. Naphthoyl substituents include 4- and 7-alkyl groups as well as 2-, 4-, 6-, 7-methoxy and 4-ethoxy groups. The effects of these substituents on receptor affinities are discussed and structure-activity relationships are presented. In the course of this work three new highly selective CB(2) receptor agonists were identified, 1-propyl-3-(4-methyl-1-naphthoylindole (JWH-120), 1-propyl-2-methyl-3-(6-methoxy-1-naphthoylindole (JWH-151), and 1-pentyl-3-(2-methoxy-1-naphthoylindole (JWH-267). GTPgammaS assays indicated that JWH-151 is a full agonist at CB(2), while JWH-120 and JWH-267 are partial agonists. Molecular modeling and receptor docking studies were carried out on a set of 3-(4-propyl-1-naphthoyl)indoles, a set of 3-(6-methoxy-1-naphthoyl)indoles and the pair of N-pentyl-3-(2-methoxy-1-naphthoyl)indoles. Docking studies indicated that the CB(1) receptor affinities of these compounds were consistent with their aromatic stacking interactions in the aromatic microdomain of the CB(1) receptor. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect