Synthesis and evaluation of peptide–fentanyl analogue conjugates as dual µ/δ-opioid receptor agonists for the treatment of pain

Li, Jing; Zhang, Tao; Sun, Jianjun; Ren, Fengxia; Jia, Hongxin; Yu, Zixing; Cheng, Jingchao; Shi, Weiguo

doi:10.1016/j.cclet.2021.11.036

Cited by 4 publications

(2 citation statements)

References 17 publications

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“…Notably however, some progress in their syntheses have been reported in several past years [ 124 , 125 , 126 , 127 ]. Moreover, in the field of mixed opioid ligands, there is an interesting recent example, in which carfentanil ( 1.2 ) fragments were hybridized with peptide dermorphine analogues to yield potent analgesics with improved properties [ 128 ].…”

Section: Discussionmentioning

confidence: 99%

Fentanyl Structure as a Scaffold for Opioid/Non-Opioid Multitarget Analgesics

Lipiński

Matalińska

2022

IJMS

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One of the strategies in the search for safe and effective analgesic drugs is the design of multitarget analgesics. Such compounds are intended to have high affinity and activity at more than one molecular target involved in pain modulation. In the present contribution we summarize the attempts in which fentanyl or its substructures were used as a μ-opioid receptor pharmacophoric fragment and a scaffold to which fragments related to non-opioid receptors were attached. The non-opioid ‘second’ targets included proteins as diverse as imidazoline I2 binding sites, CB1 cannabinoid receptor, NK1 tachykinin receptor, D2 dopamine receptor, cyclooxygenases, fatty acid amide hydrolase and monoacylglycerol lipase and σ1 receptor. Reviewing the individual attempts, we outline the chemistry, the obtained pharmacological properties and structure-activity relationships. Finally, we discuss the possible directions for future work.

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Section: Discussionmentioning

confidence: 99%

Fentanyl Structure as a Scaffold for Opioid/Non-Opioid Multitarget Analgesics

Lipiński

Matalińska

2022

IJMS

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“…administration on day 5, the mice were administered naloxone (2 mg/kg, intraperitoneally i.p. ), and the number of vertical jumps was tallied over a 20 min duration to evaluate the physical dependence on the test compound [24,25].…”

Section: Physical Dependencementioning

confidence: 99%

Synthesis and Biological Evaluation of Novel Biased Mu-Opioid Receptor Agonists

Guo,

Yu,

Zhang

et al. 2024

Molecules

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This study explored the potential of a series of PZM21 analogues for pain treatment. Specifically, the hydroxyphenyl ring of PZM21 was replaced with a naphthyl ring, the thienyl ring was substituted with either a phenyl ring or furan rings, and the essential dimethylamine and urea groups were retained. These compounds aimed to enhance safety and minimize the adverse effects associated with opioid drugs. The research findings suggest that compound 6a does not induce β-arrestin recruitment at low-nanomolar concentrations but exhibits significant analgesic effects in established mouse models. Compared to morphine, 6a shows advantages in alleviating respiratory depression and minimizing physical dependence. Molecular docking studies underscore the pivotal role of the D147 amino acid residue in the analgesic mechanism of 6a. Consequently, 6a is a compelling candidate for the development of safer opioid analgesics and warrants further attention.

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