Role of efficacy as a determinant of locomotor activation by mu‐opioid receptor (MOR) ligands in female and male mice. II. Effects of novel MOR‐selective phenylmorphans with high‐to‐low MOR efficacy

Abstract

Low‐efficacy mu‐opioid receptor (MOR) agonists represent promising therapeutics, but existing compounds (e.g., buprenorphine, nalbuphine) span a limited range of low MOR efficacies and have poor MOR selectivity. Accordingly, new and selective low‐efficacy MOR agonists are of interest. A novel set of chiral C9‐substituted phenylmorphans has been reported to display improved MOR selectivity and a range of high‐to‐low MOR efficacies under other conditions; however, a full opioid receptor binding profile for these drugs has not been described. Additionally, studies in mice will be useful for preclinical characterization of these novel compounds, but the pharmacology of these drugs in mice has also not been examined. Accordingly, the present study characterized the binding selectivity and in vitro efficacy of these compounds using assays of opioid receptor binding and ligand‐stimulated [35S]GTPɣS binding. Additionally, locomotor effects were evaluated as a first step for in vivo behavioral assessment in mice. The high‐efficacy MOR agonist and clinically effective antidepressant tianeptine was included as a comparator. In binding studies, all phenylmorphans showed improved MOR selectivity relative to existing lower‐efficacy MOR agonists. In the ligand‐stimulated [35S]GTPɣS binding assay, seven phenylmorphans had graded levels of sub‐buprenorphine MOR efficacy. In locomotor studies, the compounds again showed graded efficacy with a rapid onset and ≥1 h duration of effects, evidence for MOR mediation, and minor sex differences. Tianeptine functioned as a high‐efficacy MOR agonist. Overall, these in vitro and in vivo studies support the characterization of these compounds as MOR‐selective ligands with graded MOR efficacy and utility for further behavioral studies in mice.

A MOR Antagonist with High Potency and Antagonist Efficacy among Diastereomeric C9-Alkyl-Substituted N-Phenethyl-5-(3-hydroxy)phenylmorphans

“…Melting points were determined on a Mettler Toledo MP70 and are uncorrected. Proton and carbon nuclear magnetic resonance ( 1 H and 13 C NMR) spectra (Figures S1-S12 in Supplementary Material) were recorded on a Varian Gemini-400 spectrometer in CDCl 3 (unless otherwise noted) with the values given in ppm (TMS as internal standard) and J (Hz) assignments of 1 H resonance coupling. The analyses were performed on the free base, unless otherwise noted.…”

“…The HCl salt of 15 was formed in iPrOH with 37% HCl (0.1 mL) and recrystallized from ethanol to give a white solid: mp 247-250 • C. 1 H NMR (400 MHz; CD 3 OD): δ 7.39-7.33 (m, 4H), 7.32-7.26 (m, 1H), 7.18-7.15 (m, 1H), 6.80 (t, J = 5.6 Hz, 1H), 6.76 (s, 1H), 6.65 (dd, J = 8.0, 2.0 Hz, 1H), 3.93-3.92 (m, 1H), 3.73-3.51 (m, 3H), 3.44-3.35 (m, 1H), 3.25-3.17 (m, 1H), 3.06-2.98 (m, 1H), 2.51-2.39 (m, 2H), 2.31-2.21 (m, 2H), 2.11-1.99 (m, 3H), 1.90-1.82 (m, 2H), 1.48-1.40 (m, 1H), 1.29-1.23 (m, 1H), 1.19 (d, J = 7.0 Hz), and 0.90 (t, J = 7.4 Hz, 3H). 13 (17). The HCl salt of alkene 11 (273 mg,1 equiv, 663 µmol) was was hydrogenated according to the general procedure using palladium on carbon (Escat 103) (4.02 mg, 0.1 equiv, 37.8 µmol) to afford 17 as a white foam (230 mg, 92% yield).…”

“…The HCl salt of 18 was formed in iPrOH with 37% HCl (0.1 mL) and recrystallized from ethanol to give a white solid: mp 249-253 • C. 1 H NMR (400 MHz; CD 3 OD): δ 7.39-7.34 (m, 4H), 7.32-7.26 (m, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.85-6.81 (m, 1H), 6.66 (dd, J = 8.0, 2.2 Hz, 1H), 3.81 (s, 1H), 3.71-3.58 (m, 2H), 3.58-3.46 (m, 2H), 3.19-3.11 (m, 2H), 2.40-2.32 (m, 2H), 2.18-1.89 (m, 7H), 1.40-1.31 (m, 1H), 1.22-1.14 (m, 1H), and 0.86 (t, J = 7.5 Hz, 3H). 13…”

“…The HCl salt of 19 was formed in iPrOH (1 mL) with 37% HCl (0.1 mL) and recrystallized from hot ethanol (4 mL) to give a white solid: mp 240-242 • C; 1 H NMR (400 MHz; CD 3 OD): δ 7.37-7.33 (m, 4H), 7.28 (dt, J = 8.6, 4.3 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H), 6.89-6.84 (m, 2H), 6.66 (dd, J = 8.0, 2.0 Hz, 1H), 3.76 (s, 1H), 3.65-3.58 (m, 2H), 3.54-3.49 (m, 2H), 3.20-3.13 (m, 2H), 2.55 (d, J = 10.2 Hz, 1H), 2.42-2.35 (m, 1H), 2.18-1.91 (m, 8H), 1.40-1.30 (m, 2H), 1.20-1.00 (m, 2H), 0.83 (t, J = 7.1 Hz, 3H). 13 ). 3-((1S,5R,9S)-9-Butyl-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol (20).…”

“…The tartrate salt of 20 was formed in iPrOH with D-tartaric acid and recrystallized from hot ethanol to give a white solid: mp 193-196 • C. 1 H NMR (400 MHz; CD 3 OD): δ 7.35-7.32 (m, 4H), 7.26 (ddd, J = 8.4, 5.7, 2.9 Hz, 1H), 7.15 (dd, J = 10.4, 6.0 Hz, 1H), 6.87 (d, J = 7.0 Hz, 2H), 6.66-6.64 (m, 1H), 4.47 (s, 2H), 3.75 (s, 1H), 3.63-3.58 (m, 2H), 3.48 (dd, J = 10.5, 6.2 Hz, 2H), 3.18-3.11 (m, 2H), 2.52-2.37 (m, 2H), 2.18-2.01 (m, 4H), 2.00-1.88 (m, 3H), 1.35-1.03 (m, 7H), 0.80 (t, J = 6.9 Hz, 3H). 13 35). The HCl salt of alkene 29 (300 mg,1 equiv, 781 µmol) was dissolved in MeOH (15 mL) and was hydrogenated according to the general procedure using palladium on carbon (Escat 103) (8.31 mg, 0.1 equiv, 78.1 µmol) to afford 36 and isolated as a white foam (250 mg, 91% yield).…”