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

Abstract

Based on 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 non-conserved 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.

Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands

“…The competitive radioligand binding assays were performed as described previously. 36, 37 To compare with previous results as well as for consistency purpose, [ 3 H]naloxone (NLX), [ 3 H]naltrindole (NTI), and [ 3 H]diprenorphine (DPN) were used to label the MOR, DOR and KOR, respectively. The MOR [ 35 S]GTPγS binding assay was conducted to determine the efficacy of each ligand at the MOR as reported earlier.…”

“…36,37 Briefly, for the competition binding assay, [ 3 H]NLX, [ 3 H]DPN, and [ 3 H]NTI were used to label the MOR, the KOR, and the DOR, respectively. Aliquots of a membrane protein (30 µg) were incubated with the corresponding radioligand in the presence of different concentrations of the ligand under investigation in TME buffer (50 mM Tris, 3 mM MgCl 2 , 0.2 mM EGTA, pH 7.7) at 30 °C for 1.5 h. The bound radioactive ligand was separated from the free radioligand by filtration using the Brandel harvester (Biomedical Research & Development Laboratories, MD).…”

Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site

“…The β-dihydrocodeine amine two was treated to m -iodobenzoic acid in the presence coupling reagent HATU with an organic base DIPEA to furnish corresponding m -iodoarylamidomorphinan 3. The m -iodoarylamidomorphinan three was treated with DIAD at 65°C in acetonitrile for 20 hr followed by two equivalents of pyridine hydrochloride (Py.HCl) treatment at room temperature to obtain the m -iodoarylamidonormorphinan 4 ( Yuan et al, 2013 ). N -alkylation of 4 was achieved by heating it with (bromomethyl)cyclopropane in the presence of K 2 CO 3 in DMF to furnish 5 .…”

Iridium-Catalyzed Csp3–H Activation for Mild and Selective Hydrogen Isotope Exchange

“…Following the catalyst activation the NMR tube was cooled to 0 °C in an ice bath prior to injection into the NMR spectrometer. 31 P NMR experiments were run at 0 °C to allow observation of changes in the active catalytic species.…”