Design, Synthesis, and Biological Evaluation of 14-Heteroaromatic-Substituted Naltrexone Derivatives: Pharmacological Profile Switch from Mu Opioid Receptor Selectivity to Mu/Kappa Opioid Receptor Dual Selectivity
- 7 November 2013
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 56 (22), 9156-9169
- https://doi.org/10.1021/jm4012214
Abstract
On the basis of a mu opioid receptor (MOR) homology model and the isosterism concept, three generations of 14-heteroaromatically substituted naltrexone derivatives were designed, synthesized, and evaluated as potential MOR-selective ligands. The first-generation ligands appeared to be MOR-selective, whereas the second and the third generation ones showed MOR/kappa opioid receptor (KOR) dual selectivity. Docking of ligands 2 (MOR selective) and 10 (MOR/KOR dual selective) to the three opioid receptor crystal structures revealed a nonconserved-residue-facilitated hydrogen-bonding network that could be responsible for their distinctive selectivity profiles. The MOR/KOR dual-selective ligand 10 showed no agonism and acted as a potent antagonist in the tail-flick assay. It also produced less severe opioid withdrawal symptoms than naloxone in morphine-dependent mice. In conclusion, ligand 10 may serve as a novel lead compound to develop MOR/KOR dual-selective ligands, which might possess unique therapeutic value for opioid addiction treatment.Keywords
Funding Information
- National Institutes of Health (DA024022)
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