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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. [Display omitted] • A series of benzylaminofentanyl derivates were synthesized as bifunctional MOR/σ 1 R ligands to develop safer analgesics. • Compound 68 showed desirable MOR agonism (EC 50 = 48.5 nΜ, E max = 66.3%) and σ 1 R antagonism (K i = 35.7 nM) in vitro. • Compound 68 exerted powerful analgesic effects in abdominal constriction test and formalin-induced pain test in rodents. • At equianalgesic doses, compound 68 induced fewer MOR-related side effects than fentanyl in mice. [ABSTRACT FROM AUTHOR]

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. [Display omitted] 1. A new series of bifunctional piperidinamide derivatives were synthesized and evaluated biological activity. 2. Compound 114 showed superior affinities for σ 1 R and MOR and good selectivity to additional receptors related to pain. 3. Compound 114 showed powerful dose-dependent analgesic effects in different models. 4. Compound 114 produced fewer opioid-like side effects, such as reward liability, respiratory depression, physical dependence and sedation than fentanyl at an equianalgesic dose. [ABSTRACT FROM AUTHOR]

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 Ca2+-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. [Display omitted] • σ 1 R antagonists exhibit anti-hypersensitive effects in sensitising pain conditions. • σ 1 R antagonists enhance opioid analgesia but not opioid-mediated unwanted effects. • Bifunctional MOR and σ 1 R ligands possess wider therapeutic window with fewer adverse effects. • Representative ligands with MOR agonist and σ 1 R antagonist activities were summarised. • Dual MOR-agonism/σ 1 R-antagonism represents a promising avenue for the development of potent and safer analgesics. [ABSTRACT FROM AUTHOR]