Benzylaminofentanyl derivates: Discovery of bifunctional μ opioid and σ1 receptor ligands as novel analgesics with reduced adverse effects

• Published in: European journal of medicinal chemistry 2022-11, Vol.241, p.114649-114649, Article 114649
• Main Authors: Zhuang, Tao, Xiong, Jiaying, Ren, Xia, Liang, Lingzhi, Qi, Zhaoyang, Zhang, Shuang, Du, Wei, Chen, Yin, Liu, Xin, Zhang, Guisen
• Format: Article
• Language: English
• Subjects: Analgesic; Benzylaminofentanyl derivates; Bifunctional ligands; Side effects; μ opioid receptor; σ1 receptor
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114649

To develop safer and potent analgesics, we designed, synthesized, and evaluated a new series of benzylaminofentanyl derivates as bifunctional μ opioid receptor (MOR) and σ1 receptor (σ1R) ligands. Compound 68 (Tao-191) showed desirable MOR agonism (Ki = 6.5 nΜ; EC50 = 48.5 nΜ, Emax = 66.3%) and σ1R antagonism (Ki = 35.7 nM) in vitro, and exerted powerful analgesic effects in the abdominal constriction test (ED50 = 0.32 mg/kg, in mice), formalin-induced pain test (phase II, ED50 = 2.26 mg/kg, in rats), and paclitaxel-induced neuropathic pain model (ED50 = 0.30 mg/kg, in mice). The contributions of MOR and σ1R to its antinociceptive effect were verified by combined administration with the MOR antagonist naloxone and the σ1R 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/σ1R 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/σ1R ligands to develop safer analgesics.•Compound 68 showed desirable MOR agonism (EC50 = 48.5 nΜ, Emax = 66.3%) and σ1R antagonism (Ki = 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.