Dezocine is becoming dominated in China market for relieving moderate to severe pain. It is believed that Dezocine's clinical efficacy and little chance to provoke adverse events during the therapeutic process are mainly attributed to its partial agonist activity at the μ opioid receptor. In the present work, we comprehensively studied the pharmacological characterization of Dezocine and identified that the analgesic effect of Dezocine was a result of action at both the κ and μ opioid receptors. We firstly found that Dezocine displayed preferential binding to μ opioid receptor over κ and δ opioid receptors. Dezocine, on its own, weakly stimulated G protein activation in cells expressing κ and μ receptors, but in the presence of full κ agonist U50,488 H and μ agonist DAMGO, Dezocine inhibited U50,488H- and DAMGO-mediated G protein activation, indicating that Dezocine was a κ partial agonist and μ partial agonist. Then the in intro results were verified by in vivo studies in mice. We observed that Dezocine-produced antinociception was significantly inhibited by κ antagonist nor-BNI and μ antagonist β-FNA pretreatment, indicating that Dezocine-mediated antinociception was via both the κ and μ opioid receptors. When co-administrating of Dezocine with U50,488 H or morphine, Dezocine was capable of inhibiting U50,488H- or morphine-induced antinociception. Finally, κ receptor activation-associated side effect sedation was investigated. We found that Dezocine displayed limited sedative effect with a ceiling effecting at a moderate dose. Thus, our work led to a better understanding of the analgesic mechanism of action of Dezocine in vivo.

To develop novel analgesics with no side effects or less side effects than traditional opioids is highly demanded to treat opioid receptor mediated pain and addiction issues. Recently, κ-opioid receptor (KOR) has been established as an attractive target, although its selective agonists could bear heterogeneous pharmacological activities. In this study, we designed and synthesized two new series of nepenthone derivatives by inserting a spacer (carbonyl) between 6α,14α-endo-ethenylthebaine and the 7α-phenyl substitution of the skeleton and by substituting the 17-N-methyl group with a cyclopropylmethyl group. We performed in vitro tests (binding and functional assays) and molecular docking operations on our newly designed compounds. The results of wet-experimental measures and modeled binding structures demonstrate that these new compounds are selective KOR agonists with nanomolar level affinities. Compound 4 from these new derivatives showed the highest affinity (K = 0.4 ± 0.1 nM) and the highest selectivity (μ/κ = 339, δ/κ = 2034) toward KOR. The in vivo tests revealed that compound 4 is able to induce stronger (ED = 2.1 mg/kg) and much longer antinociceptive effect than that of the typical KOR agonist U50488H (ED = 4.4 mg/kg). Therefore, compound 4 can be used as a perfect lead compound for future design of potent analgesics acting through KOR.

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