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

Tao Zhuang; Jiaying Xiong; Xia Ren; Lingzhi Liang; Zhaoyang Qi; Shuang Zhang; Wei Du; Yin Chen; Xin Liu; Guisen Zhang

doi:10.1016/j.ejmech.2022.114649

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

Eur J Med Chem. 2022 Nov 5:241:114649. doi: 10.1016/j.ejmech.2022.114649. Epub 2022 Aug 5.

Authors

Tao Zhuang¹, Jiaying Xiong², Xia Ren³, Lingzhi Liang³, Zhaoyang Qi³, Shuang Zhang⁴, Wei Du⁵, Yin Chen⁶, Xin Liu⁷, Guisen Zhang⁸

Affiliations

¹ Jiangsu Key Laboratory of Marine Biological Resources and Environment, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China; Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
² School of Medicine, Guangxi University of Science and Technology, Liuzhou, 545005, China.
³ Jiangsu Key Laboratory of Marine Biological Resources and Environment, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China.
⁴ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
⁵ Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
⁶ Jiangsu Key Laboratory of Marine Biological Resources and Environment, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China. Electronic address: 2019000015@jou.edu.cn.
⁷ Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China. Electronic address: xliu@mail.hust.edu.cn.
⁸ Jiangsu Key Laboratory of Marine Biological Resources and Environment, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China; Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China. Electronic address: gszhang@mail.hust.edu.cn.

PMID: 35961067
DOI: 10.1016/j.ejmech.2022.114649

Abstract

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 (K_i = 6.5 nΜ; EC₅₀ = 48.5 nΜ, E_max = 66.3%) and σ₁R antagonism (K_i = 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.

Keywords: Analgesic; Benzylaminofentanyl derivates; Bifunctional ligands; Side effects; μ opioid receptor; σ(1) receptor.

MeSH terms

Analgesics* / pharmacology
Animals
Ligands
Mice
Naloxone / pharmacology
Neuralgia*
Rats
Receptors, Opioid, mu* / agonists
Receptors, Opioid, mu* / antagonists & inhibitors
Receptors, sigma* / agonists
Receptors, sigma* / antagonists & inhibitors
Sigma-1 Receptor

Substances

Analgesics
Ligands
Receptors, Opioid, mu
Receptors, sigma
Naloxone