Novel κ-opioid receptor agonist MB-1C-OH produces potent analgesia with less depression and sedation

Abstract

Aim: To characterize the pharmacological profiles of a novel κ-opioid receptor agonist MB-1C-OH. Methods: [ 3 H]diprenorphine binding and [ 35 S]GTPγS binding assays were performed to determine the agonistic properties of MB-1C-OH. Hot plate, tail flick, acetic acid-induced writhing, and formalin tests were conducted in mice to evaluate the antinociceptive actions. Forced swimming and rotarod tests of mice were used to assess the sedation and depression actions. Results: In [ 3 H]diprenorphine binding assay, MB-1C-OH did not bind to μ-and δ-opioid receptors at the concentration of 100 μmol/L, but showed a high affinity for κ-opioid receptor (K i =35 nmol/L). In [ 35 S]GTPγS binding assay, the compound had an E max of 98% and an EC 50 of 16.7 nmol/L for κ-opioid receptor. Subcutaneous injection of MB-1C-OH had no effects in both hot plate and tail flick tests, but produced potent antinociception in the acetic acid-induced writhing test (ED 50 =0.39 mg/kg), which was antagonized by pretreatment with a selective κ-opioid receptor antagonist Nor-BNI. In the formalin test, subcutaneous injection of MB-1C-OH did not affect the flinching behavior in the first phase, but significantly inhibited that in the second phase (ED 50 =0.87 mg/kg). In addition, the sedation or depression actions of MB-1C-OH were about 3-fold weaker than those of the classical κ agonist (-)U50,488H. Conclusion: MB-1C-OH is a novel κ-opioid receptor agonist that produces potent antinociception causing less sedation and depression.

Characterization of Sigma 1 Receptor Antagonist CM-304 and Its Analog, AZ-66: Novel Therapeutics Against Allodynia and Induced Pain

“…Alternatively, the sigma-receptor antagonists might indirectly affect respiration by decreasing locomotor activity. AZ-66 demonstrated disruption of coordinated locomotion in the rotarod assay, similar to U50,488, an agent known to produce motor incoordination and sedation (Zhang et al, 2015; Dunn et al, 2018). However, CM-304 was without significant inhibitory effects on locomotion, and in any case, the potential sedative effects of sigma-receptor antagonists are also not well understood.…”

Evaluation of Biased and Balanced Salvinorin A Analogs in Preclinical Models of Pain

“…Despite these advantages, traditional KOPr agonists, such as U50,488, that have balanced signaling properties ( Schattauer et al, 2012 ), are associated with many side effects including sedation, anxiety, aversion, and dysphoria limiting their clinical development ( Mucha and Herz, 1985 ; Pfeiffer et al, 1986 ; Suzuki et al, 1992 ; Bals-Kubik et al, 1993 ; Privette and Terrian, 1995 ; Pande et al, 1996 ; Skoubis et al, 2001 ; Walsh et al, 2001 ; Mague et al, 2003 ; Kudryavtseva et al, 2004 ; Vunck et al, 2011 ; Ehrich et al, 2015 ; Zhang et al, 2015 ; Wang et al, 2016 ). The concept of biased agonism, whereby activation of a G-protein coupled receptor can result in differential activation of signal transduction pathways, suggests that it may be possible to separate desired physiological effects from adverse side effects.…”

The analgesic and anti‐inflammatory effects of Salvinorin A analogue β‐tetrahydropyran Salvinorin B in mice

“…Development of KOPr agonists with fewer side-effects (Law et al, 2013; Zhang et al, 2015) and reduced abuse potential (Morani et al, 2009) have recently received increased attention (Kivell and Prisinzano, 2010; Tsukahara-Ohsumi et al, 2011; Váradi et al, 2015; White et al, 2015). The recent clinical success of the potent KOPr agonist nalfurafine (Seki et al, 1999; Kumagai et al, 2010) illustrates the clinical utility of KOPr agonists for the management of pain and pruritus.…”