Characterization of a Potential KOR/DOR Dual Agonist with No Apparent Abuse Liability via a Complementary Structure–Activity Relationship Study on Nalfurafine Analogues

Abstract

Discovery of analgesics void of abuse liability is critical to battle the opioid crisis in the United States. Among many strategies to achieve this goal, targeting more than one opioid receptor seems promising to minimize this unwanted side effect while achieving a reasonable therapeutic profile. In the process of understanding the structure−activity relationship of nalfurafine, we identified a potential analgesic agent, NMF, as a dual kappa opioid receptor/delta opioid receptor agonist with minimum abuse liability. Further characterizations, including primary in vitro ADMET studies (hERG toxicity, plasma protein binding, permeability, and hepatic metabolism), and in vivo pharmacodynamic and toxicity profiling (time course, abuse liability, tolerance, withdrawal, respiratory depression, body weight, and locomotor activity) further confirmed NMF as a promising drug candidate for future development.

Systematic Structure–Activity Relationship Study of Nalfurafine Analogues toward Development of Potentially Nonaddictive Pain Management Treatments

“…With an antinociceptive potency similar to compound 21, NMF showed antinociceptive effects for 1 h at a dose of 0.1 mg/kg. 28 Comparatively, both 0.1 mg/kg compound 21 and 0.5 mg/kg compound 23 (with increased potency as previously discussed) had a duration of action of 3 h. Thus, both compounds 21 and 23 have longer durations of antinociceptive action than 10 mg/kg morphine, 0.1 mg/kg NLF, and 0.1 mg/kg NMF in the WWTI assay. 106 To determine which opioid receptors mediated these potentially antinociceptive effects, a receptor selectivity study was done.…”

“…108 Compounds 21 and 23 were approximately equipotent to more potent than both NLF and NMF (Table 3). 28 Interestingly, seven out of the nine compounds that were selected for dose-dependence study bear the R 2 methyl group suggesting that the presence of this methyl group may also be important for in vivo antinociceptive potency. The remaining two aid in forming this conclusion via comparison to their more potent methyl-bearing counterparts (22 vs 21; 24 vs 23).…”

“…This agrees with the results of our previously published study on 8 structurally similar compounds as well wherein NLF and NMF also contain this methyl group. 28 The two most potent compounds in the WWTI assay (21 and 23) were further studied to determine the antinociceptive time course. Here, the test compound was injected subcutaneously, and withdrawal latencies were recorded at subsequent time points to determine the duration of compound effects following published protocol.…”

“…Herein, mice were treated with selective opioid receptor antagonists prior to testing with compound 21 or 23 following previously published protocol. 28,29 Specifically, the MOR antagonist β-funaltrexamine (β-FNA), the KOR antagonist nor-binaltorphimine (nor-BNI), and the DOR antagonist naltrindole (NTI) were subcutaneously injected prior to the subcutaneous injection of compound followed by measurement of withdrawal latency 20 min later. 110−112 Figure 4 shows that when NTI and nor-BNI were administered separately prior to NLF administration, the resulting MPEs were significantly lower than those when NLF was administered alone indicating the involvement of the DOR and the KOR, respectively.…”

“…Withdrawal latencies for mice in all groups were acquired 20 min post-testcompound administration. 28,29 Time-Course Study. Baseline tail withdrawal latencies were measured according to the "general" procedure 1 h prior to s.c. administration of test compound.…”