Novel Molecular Targets of Dezocine and Their Clinical Implications

Abstract

Background While dezocine is a partial mu opioid receptor agonist, it is not a controlled substance. Thus, the characterization of the molecular targets of dezocine is critical for scientific and clinical implications. The goal of this study is to characterize molecular targets for dezocine and their implications. Methods A binding screen for dezocine was performed on 44 available receptors and transporter proteins. Functional assays for the novel targets were performed along with computation calculations to locate the binding site. A G protein activation study was performed for the human kappa opioid receptor to determine whether dezocine is a kappa antagonist. Data are presented as mean ± SE. Results The affinities for dezocine were 3.7±0.7 nM for the mu receptor, 527±70 nM for the delta receptor, and 31.9±1.9 nM for the kappa receptor. Dezocine failed to induce G protein activation with kappa opioid receptor and concentration dependently inhibited kappa agonist (salvinorin A and nalbuphine) induced receptor activation, indicating that dezocine is a kappa antagonist. Two novel molecular targets (norepinephrine transporter, NET; and serotonin transporter, SERT) were identified. Dezocine concentration-dependently inhibited norepinephrine and serotonin reuptake in vitro. The half maximal inhibitory concentrations (expressed as pIC50) were 5.68±0.11 for NET and 5.86 ± 0.17 for SERT. Dezocine occupied the binding site for known NET and SERT inhibitors. Conclusions The unique molecular pharmacological profile of dezocine as a partial mu receptor agonist, a kappa receptor antagonist and a norepinephrine and serotonin reuptake inhibitor (via NET and SERT) was revealed. These discoveries reveal potentially important novel clinical implications and drug interactions of dezocine.

Dezocine prevents sufentanil-induced cough during general anesthesia induction: A randomized controlled trial

“…Dezocine, a partial m-agonist and k-antagonist, has been discovered two novel molecular targets: the norepinephrine transporter and the serotonin transporter [9]. The current study found that the incidence and the severity of coughing were significantly higher in patients administered normal saline than in those administered dezocine during general anesthesia induction.…”

“…Interestingly, no cough was observed in Group D. This result suggests that dezocine may present an effective way to prevent the occurrence and reflex degree of sufentanil-induced irritating cough in general anesthesia induction. A possible explanation for this phenomenon is that dezocine suppresses sufentanil-induced cough by k-receptor antagonism or inhibits norepinephrine and serotonin reuptake [9], which in turn antagonize sufentanil-activated m receptors, reducing cough. The current results also show that sufentanil-induced cough may be mainly related to the m-opioid receptor mediated by…”

“…Dezocine is an analgesic, acting as partial antagonist of k-receptors and agonist of m-receptors [9]. Previous studies have reported that dezocine can effectively reduce fentanyl-induced cough [10].…”

Comparison of Cardiovascular, Analgesic and Sedative Effects of Different Doses of Dezocine

“…Dezocine, as an opioidmu receptor partial agonist/antagonist, is considered to be an alternative medication for managing postoperative pain. Common adverse effects observed in opioids with full agonism are significantly reduced due to its partial agonism on the mu opioid receptor [1][2][3][4]. Similar to other opioids, Dezocine could decrease anesthetic requirement by up to 50% [5].…”

Antinociceptive effects of dezocine on complete Freund's adjuvant‑induced inflammatory pain in rats

“…A previous study has demonstrated that dezocine may be a novel molecular target, with clinical implications (10). Dezocine was also revealed to antagonize morphine analgesia upon simultaneous administration in mice models of acute nociception (11).…”