期刊
CHEMMEDCHEM
卷 17, 期 7, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202100684
关键词
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资金
- National Institute of General Medical Sciences [P30GM122733]
- National Institute of General Medical Sciences (Neuropharmacology Core Facility at the University of Mississippi, School of Pharmacy)
- Department of BioMolecular Sciences at the University of Mississippi, School of Pharmacy
This study introduces a method to create compounds with dual agonism on opioid receptors. In vitro and in vivo studies show that these compounds have analgesic activity while avoiding harmful side effects.
Current common analgesics are mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. However, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold via an ester linker. In vitro studies showed that many of these compounds have dual agonism on kappa and mu opioid receptors. In vivo studies on the lead dual kappa and mu opioid receptor agonist demonstrated supraspinal thermal analgesic activity while avoiding anxiogenic effects in male mice, thus providing further strong evidence in support of the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.
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