Table 1. Opioid Receptor Binding, Functional Activities, Antinociceptive Potencies, and Physicochemical Properties of N-Methylmorphinan-6-ones 1–4 and Their 6-Desoxo Counterparts 1a–4a.
| opioid receptor binding, Ki (nM)a,c |
|
||||||||
|---|---|---|---|---|---|---|---|---|---|
| affinity |
selectivity |
functional activityb,c [35S]GTPγS MOR |
antinociceptive activityd hot-plate assay | ||||||
| compd | MOR | DOR | KOR | DOR/MOR | KOR/MOR | EC50 (nM) | % stim | ED50 (μg/kg, sc) (95% CI) | clogP e |
| 1 | 1.79 ± 0.34 | 70.0 ± 4.1 | 25.3 ± 8.4 | 39 | 14 | 7.80 ± 1.61 | 91.5 ± 5.0 | 382 (186–785) | 0.88 |
| 1a | 1.65 ± 0.5 | 201 ± 80 | 21.6 ± 3.9 | 122 | 13 | 8.99 ± 2.19 | 104 ± 7 | 383 (209–802) | 1.24 |
| 2 | 0.32 ± 0.08 | 8.80 ± 0.35 | 10.1 ± 3.1 | 28 | 32 | 1.45 ± 0.32 | 96.4 ± 5.0 | 14.2 (7.75–26.1) | 1.45 |
| 2a | 0.24 ± 0.08 | 8.64 ± 2.25 | 3.99 ± 0.63 | 36 | 17 | 1.37 ± 0.26 | 105 ± 6 | 17.3 (8.68–34.4) | 1.82 |
| 3 | 0.45 ± 0.10 | 1.05 ± 0.42 | 1.27 ± 0.24 | 2.3 | 2.8 | 0.32 ± 0.16 | 101 ± 5 | 2.38 (1.29–4.38) | 3.23 |
| 3a | 0.048 ± 0.011 | 0.89 ± 0.29 | 0.85 ± 0.05 | 21 | 18 | 0.13 ± 0.03 | 103 ± 8 | 2.41 (1.39–4.17) | 3.60 |
| 4 | 0.25 ± 0.04 | 19.8 ± 1.3 | 15.1 ± 0.9 | 79 | 60 | 3.28 ± 0.81 | 99.2 ± 2.8 | 27.1 (12.7–58.1) | 1.66 |
| 4a | 0.34 ± 0.08 | 12.9 ± 1.6 | 7.92 ± 4.47 | 38 | 23 | 2.95 ± 0.54 | 104 ± 3 | 25.1 (13.0–48.5) | 1.90 |
a
Determined in competition binding assays using membranes from CHO cells expressing human opioid receptors.
b
Determined in the [35S]GTPγS binding assay using CHO-hMOR cell membranes. Percentage stimulation (% stim) relative to the MOR full agonist DAMGO.
c
Values are the mean ± SEM of at least three independent experiments.
d
Determined in the hot-plate assay in mice at peak effect (30 min) after sc drug administration (n = 5–6 mice per group).
e
Calculated logP (clogP) using MarvinSketch 17.10 (ChemAxon, www.chemaxon.com).