6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects

Abstract

Current common analgesics are mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. However, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold via an ester linker. In vitro studies showed that many of these compounds have dual agonism on kappa and mu opioid receptors. In vivo studies on the lead dual kappa and mu opioid receptor agonist demonstrated supraspinal thermal analgesic activity while avoiding anxiogenic effects in male mice, thus providing further strong evidence in support of the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

Figure 1.

Structures of salvinorin A, herkinorin, compound 3k,^[12] PR-38, and salvindolin.

Figure 2.

Introduction of various 6,5-fused rings to C2 of the salvinorin scaffold via an ester linker: structures of compounds 1–14.

Figure 3.

Structure-activity relationship of 6,5-fused rings on the binding affinity towards opioid receptors: (A) non-nitrogenous 6,5-fused rings; (B) 6,5-fused rings that have an additional heteroatom besides nitrogen; (C) fluorine substitutions on the indole ring; (D) breaking the trigonal planar geometry of carbon 2 on the indole ring.

Figure 4.. Effects of compounds 2 and 10 in the hot plate and tail-flick thermal anti-nociception assays.

Average latency to hind paw lick or flutter in the hot plate assay (A) or latency to withdraw tail in the tail-flick assay (B) following dosing with vehicle (n=10 for both assays), morphine (5 mg/kg, n=5 for hot plate, n=10 for tail-flick), salvinorin A (2.5 mg/kg, n=5 for both assays), herkinorin (5 mg/kg, n=10 for both assays), compound 2 (2 mg/kg, n=8 for hot plate, n=7 for tail-flick), or compound 10 (2.5 mg/kg, n=10 for both assays). All data were analyzed via one-way ANOVA, * indicates significant difference from vehicle, p<0.05.

Figure 5.. Effects of compounds 2and 10in the elevated plus maze anxiety-like behavior assay.

The average time spent in the open arms (A), distance traveled (B), and velocity (C) in the elevated plus maze following dosing with vehicle (n=10), salvinorin A (2.5 mg/kg, n=10), herkinorin (5 mg/kg, n=10), compound 2 (5 mg/kg, n=10), or compound 10 (5 mg/kg, n=10). All data were analyzed via one-way ANOVA, * indicates significant difference from vehicle, p<0.05.

Scheme 1.

Synthesis of compounds 1–10 (A), 11–12 (B), and 13–14 (C).