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To develop safer and potent analgesics, we designed, synthesized, and evaluated a new series of benzylaminofentanyl derivates as bifunctional μ opioid receptor (MOR) and σ 1 receptor (σ 1 R) ligands. Compound 68 (Tao-191) showed desirable MOR agonism (K i  = 6.5 nΜ; EC 50  = 48.5 nΜ, E max  = 66.3%) and σ 1 R antagonism (K i  = 35.7 nM) in vitro, and exerted powerful analgesic effects in the abdominal constriction test (ED 50  = 0.32 mg/kg, in mice), formalin-induced pain test (phase II, ED 50  = 2.26 mg/kg, in rats), and paclitaxel-induced neuropathic pain model (ED 50  = 0.30 mg/kg, in mice). The contributions of MOR and σ 1 R to its antinociceptive effect were verified by combined administration with the MOR antagonist naloxone and the σ 1 R agonist PRE-084, respectively. At equianalgesic doses, compound 68 induced fewer MOR-related side effects-including physical and psychological dependence, respiratory depression, constipation, and acute hyperlocomotion-than fentanyl. The results provide a rationale for further exploration of the action and safety of dual MOR/σ 1 R ligands as a promising avenue for the development of potent and safe analgesics., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Here, we describe the optimization, synthesis, and associated pharmacological analgesic activities of a new series of bifunctional piperidinamide derivatives as sigma-1 receptor (σ 1 R) antagonists and mu opioid receptor (MOR) agonists. The new compounds were evaluated in vitro in σ 1 R and MOR binding assays. The most promising compound 114 (also called HKC-126), showed superior affinities for σ 1 R and MOR and good selectivity to additional receptors related to pain. Compound 114 showed powerful dose-dependent analgesic effects in the acetic acid writhing test, formalin test, hot plate test, and chronic constriction injury (CCI) neuropathic pain model. In contrast to an equianalgesic dose of fentanyl, compound 114 produced fewer opioid-like side effects, such as reward liability, respiratory depression, physical dependence, and sedation. Lastly, the pharmacokinetic properties of this drug were also acceptable, and these results suggest that compound 114, as a mixed σ 1 R/MOR ligand, has potential for treating neuropathic pain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Opioid analgesics are highly effective painkillers for the treatment of moderate or severe pain, but they are associated with a number of undesirable adverse effects, including the development of tolerance, addiction, constipation and life-threatening respiratory depression. The development of new and safer analgesics with innovative mechanisms of action, which can enhance the efficacy in comparison to available treatments and reduce their side effects, is urgently needed. The sigma-1 receptor (σ 1 R), a unique Ca 2+ -sensing chaperone protein, is expressed throughout pain-modulating tissues and affects neurotransmission by interacting with different protein partners, including molecular targets that participate in nociceptive signalling, such as the μ-opioid receptor (MOR), N-methyl-d-aspartate receptor (NMDAR) and cannabinoid 1 receptor (CB 1 R). Overwhelming pharmacological and genetic evidence indicates that σ 1 R antagonists induce anti-hypersensitive effects in sensitising pain conditions (e.g. chemically induced, inflammatory and neuropathic pain) and enhance opioid analgesia but not opioid-mediated detrimental effects. It has been suggested that balanced modulation of MORs and σ 1 Rs may improve both the therapeutic efficacy and safety of opioids. This review summarises the functional profiles of ligands with mixed MOR agonist and σ 1 R antagonist activities and highlights their therapeutic potentials for pain management. Dual MOR agonism/σ 1 R antagonism represents a promising avenue for the development of potent and safer analgesics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

In this study, a series of novel Isoquinolinone derivatives were synthesized as potential multi-target antipsychotics. Among these, compound 13 showed high affinity for dopamine D 2 and serotonin 5-HT 1A , 5-HT 2A , 5-HT 6 , and 5-HT 7 receptors, showed low affinity for off-target receptors (5-HT 2C , H 1 , and α 1 ), and negligible effects on ether-a-gogo-related gene (hERG; i.e., reduced QT interval prolongation). An animal behavioral study revealed that compound 13 reversed APO-induced hyperlocomotion, MK-801-induced hyperactivity, and DOI-induced head twitch. Moreover, compound 13 exhibited a high threshold for acute toxicity, a lack of tendency to induce catalepsy, and did not cause prolactin secretion or weight gain when compared to risperidone. Furthermore, in the forced swim test, tail suspension test, and novel object recognition test, treatment with compound 13 resulted in improvements in depression and cognitive impairment. In addition, compound 13 had a favorable pharmacokinetic profile in rats. Thus, the antipsychotic drug-like effects of compound 13 indicate that it may be useful for developing a novel class of drugs for the treatment of schizophrenia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

We designed and synthesized a novel series of piperidine propionamide derivatives as potent sigma-1 (σ 1 ) receptor antagonists and mu (μ) opioid receptor agonists, and measured their affinity for σ 1 and μ receptors in vitro through binding assays. The basic scaffold of the new compounds contained a 4-substituted piperidine ring and N-aryl propionamide. Compound 44, N-(2-(4-(4-fluorobenzyl) piperidin-1-yl) ethyl)-N-(4-methoxy-phenyl) propionamide, showed the highest affinity for σ 1 receptor (K i σ 1  = 1.86 nM) and μ receptor (K i μ = 2.1 nM). It exhibited potent analgesic activity in the formalin test (ED 50  = 15.1 ± 1.67 mg/kg) and had equivalent analgesic effects to S1RA (σ 1 antagonist) in a CCI model. Therefore, Compound 44, which has mixed σ 1 /μ receptor profiles, may be a potential candidate for treating neuropathic pain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)