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The compelling demand of a consummate analgesic medication without addiction is rising due to the clinical mistreatment. Additionally, the series of severe untoward effects usually deterred the utilization while coping with serious pain. As a possible turning point, we revealed that compound 14 is a dual agonist of mu opioid receptor (MOR) and nociceptin-orphanin FQ opioid peptide (NOP) receptor in this study. More importantly, compound 14 achieves pain relieving at very small doses, meanwhile, reduces several unwanted side effects such as constipation, reward, tolerance and withdrawal effects. Here, we evaluated the antinociception and side effects of this novel compound from wild type and humanized mice to further develop a safer prescription analgesic drug. [Display omitted] • Compound 14 is a bifunctional agonist of mu opioid receptor and nociceptin-orphanin FQ opioid peptide receptor. • Compound 14 exhibits robust anticonception from the thermal nociceptive mouse model. • Compound 14 validated reduced side effects such as constipation, reward, tolerance and withdrawal effects. [ABSTRACT FROM AUTHOR]

Abstract Morphine is widely used for the treatment of severe pain. This analgesic effect is mediated principally by the activation of μ-opioid receptors (MOR). However, prolonged activation of MOR also results in tolerance, dependence, addiction, constipation, nausea, sedation, and respiratory depression. To address this problem, we sought alternative ways to activate MOR – either by use of novel ligands, or via a novel activation mechanism. To this end, a series of compounds were screened using a sensitive CHO-K1/MOR/Gα15 cell-based FLIPR® calcium high-throughput screening (HTS) assay, and the bithiazole compound 5a was identified as being able activate MOR in combination with naloxone. Structural modifications of 5a resulted in the discovery of lead compound 5j , which could effectively activate MOR in combination with the MOR antagonist naloxone or naltrexone. I n vivo , naloxone in combination with 100 mg/kg of compound 5j elicited antinociception in a mouse tail-flick model with an ED 50 of 17.5 ± 4 mg/kg. These results strongly suggest that the mechanism by which the 5j /naloxone combination activates MOR is worthy of further study, as its discovery has the potential to yield an entirely novel class of analgesics. Graphical abstract Image 1 Highlights • A HTS assay identified 5a as being able to activate MOR in combination with naloxone. • Compound 5j /naloxone demonstrated anti-nociceptive effect in B6 mice. • This finding has the potential to open up a new area in pain treatment. [ABSTRACT FROM AUTHOR]

Currently, there is a significant unmet need for novel analgesics with fewer side effects. In this study, we carried out structural modification of a hit compound previously identified in an artificial-intelligence (AI) virtual screening and discovered the potent analgesic, benzo[b]thiophene-2-carboxamide analog (compound 25) with new structural scaffold. We investigated the signaling pathways of opioid receptors mediated by compound 25 , and found this racemic compound activated mu-opioid receptor through the cyclic adenosine monophosphate (cAMP) and β-arrestin-2-mediated pathways with strong potency and efficacy, and accompanying nociceptin-orphanin FQ opioid peptide and delta-opioid receptors through the cAMP pathway with weak potencies. Compound 25 elicited potent antinociception in thermal-stimulated pain (ED 50 value of 127.1 ± 34.65 μg/kg) and inflammatory-induced allodynia models with less gastrointestinal transit inhibition and antinociceptive tolerance than morphine. Overall, this study revealed a novel analgesic with reduced risks of side effects. [Display omitted] • Benzo[b]thiophene-2-carboxamides were identified as potent opioid receptor agonists. • Compound 25 demonstrates potent antinociception in thermal nociceptive mouse model. • Compound 25 exerts less potent constipation than antinociception. • Compound 25 demonstrates less antinociceptive tolerance than morphine. [ABSTRACT FROM AUTHOR]