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. 2016 Dec 22;59(24):11027-11038.
doi: 10.1021/acs.jmedchem.6b01235. Epub 2016 Dec 13.

Synthetic Studies of Neoclerodane Diterpenes From Salvia Divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic With Reduced Abuse Liability

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Synthetic Studies of Neoclerodane Diterpenes From Salvia Divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic With Reduced Abuse Liability

Rachel Saylor Crowley et al. J Med Chem. .
Free PMC article

Abstract

Opioids are widely used to treat millions suffering from pain, but their analgesic utility is limited due to associated side effects. Herein we report the development and evaluation of a chemical probe exhibiting analgesia and reduced opioid-induced side effects. This compound, kurkinorin (5), is a potent and selective μ-opioid receptor (MOR) agonist (EC50 = 1.2 nM, >8000 μ/κ selectivity). 5 is a biased activator of MOR-induced G-protein signaling over β-arrestin-2 recruitment. Metadynamics simulations of 5's binding to a MOR crystal structure suggest energetically preferred binding modes that differ from crystallographic ligands. In vivo studies with 5 demonstrate centrally mediated antinociception, significantly reduced rewarding effects, tolerance, and sedation. We propose that this novel MOR agonist may represent a valuable tool in distinguishing the pathways involved in MOR-induced analgesia from its side effects.

Figures

Figure 1
Figure 1
Many opioids are derived structurally from morphine, including codeine, oxycodone, meperidine, methadone, and fentanyl. The structure of traditional MOR agonists morphine and DAMGO differ significantly from those of the KOR agonist salvinorin A (1) and the MOR agonists herkinorin (2) and herkamide (3).
Figure 2
Figure 2
Scatter plot comparison of the pEC50 values of 2 analogues vs. 5 analogues.
Figure 3
Figure 3
The co-crystallized ligand in the active structure of the µ-opioid receptor 23 is shown in thin black lines. Insets show sections of the receptor and ligand densities in the plane normal to the membrane, and a close up of the ligand-receptor interactions, with key residues shown as gray sticks. Non-conserved residues in the κ-opioid receptor are reported in parentheses. (a) Poses of 2 in clusters 1 and 2 (in blue and pink, respectively). (b) Poses of 5 in clusters 1, 2 and 3 (in light-blue, red, and purple, respectively).
Figure 4
Figure 4
The centrally mediated antinociceptive effects of 2 and 5 were assessed in the hot-water tail-flick assay in mice at 1, 5, and 10 mg/kg, i.p., doses alongside morphine (10 mg/kg) with a 10 s time cutoff to prevent tissue injury. (a) 2 demonstrates no significant antinociceptive effects. (b) At 5 and 10 mg/kg doses, 5 produces significant antinociceptive effects, similar to that of morphine at the 10 mg/kg dose. Data shown as mean ±SEM (n=5–10 per group). ****p<0.0001, ***p<0.001, **p<0.01, *p<0.05, drug compared to vehicle.
Figure 5
Figure 5
(a) Antinociceptive effects in the hot water tail-flick assay in mice following cumulative dosing on day 1 (filled symbols) and again on day 9 (open symbols) following daily administration of 10 mg/kg/s.c. morphine or 5 (n=7). (b) Using a rotarod set to accelerate from 4 to 40 rpm over 300 s, morphine (10 mg/kg/i.p.) showed a significant decrease in motor coordination compared to 5 (10 mg/kg/i.p.) and vehicle (n=6) ****p<0.0001, ***p<0.001, **p<0.01, *p<0.05, drug compared to vehicle (b); ####p<0.0001, ###p<0.001, ##p<0.01, #p<0.05, morphine compared to 5. Data shown as mean ±SEM.
Figure 6
Figure 6
A significant place preference is seen in the morphine paired chamber at both (a) 5 mg/kg, (i.p.), and (b) 10 mg/kg, (i.p.) doses, but not with the same dose of 5 when compared to vehicle. Neither 5 (5 and 10 mg/kg) nor 2 (5 mg/kg) were significantly different to vehicle. (n=8–18). ***p<0.001, **p<0.01 compared to vehicle; #p<0.05 compared to morphine.
Scheme 1
Scheme 1
Synthetic route to compounds 4, 5, 1b, and 1c. Reagents and conditions: a) Cu(OAc)2, MeOH/CH2Cl2 (1:1); b) Pb(OAc)4, MeOH/benzene; c) RCOOH or RCOCl, DMAP, DIPEA, CH2Cl2; d) p-NO2PhCO2H, DIAD, PPh3, CH2Cl2; e) K2CO3, MeOH.
Scheme 2
Scheme 2
Synthesis of two parallel series of 2 and 5 derivatives. Reagents and conditions: a) RCO2H (2.0 equiv), EDC·HCl (2.0 equiv), DMAP (2.0 equiv), CH2Cl2, RT, 16 h.

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