Synthesis and Biological Characterization of Cyclic Disulfide-Containing Peptide Analogs of the Multifunctional Opioid/ Neuropeptide FF Receptor Agonists That Produce Long-Lasting and Nontolerant Antinociception
- 24 December 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (24), 15709-15725
- https://doi.org/10.1021/acs.jmedchem.0c01367
Abstract
In a previously described chimeric peptide, we reported that the multifunctional opioid/neuropeptide FF (NPFF) receptor agonist 0 (BN-9) produced antinociception for 1.5 h after supraspinal administration. Herein, four cyclic disulfide analogs containing L- and/or D-type cysteine at positions 2 and 5 were synthesized. The cyclized analogs and their linear counterparts behaved as multifunctional agonists at both opioid and NPFF receptors in vitro and produced potent analgesia without tolerance development. In comparison to 0, cyclized peptide 6 exhibited sevenfold more potent mu-opioid receptor agonistic activity in vitro. Interestingly, the cyclized analog 6 possessed an improved stability in the brain and an increased blood-brain barrier permeability compared to the parent peptide 0 and produced more potent analgesia after supraspinal or subcutaneous administration with improved duration of action of 4 h. In addition, antinociceptive tolerance of analog 6 was greatly reduced after subcutaneous injection compared to fentanyl, as was the rewarding effect, withdrawal reaction, and gastrointestinal inhibition.Funding Information
- National Natural Science Foundation of China (81673282, 81903430, 81973159)
- Natural Science Foundation of Gansu Province (20JR5RA310)
This publication has 62 references indexed in Scilit:
- Opioids, sensory systems and chronic painEuropean Journal of Pharmacology, 2013
- Spinal or systemic TY005, a peptidic opioid agonist/neurokinin 1 antagonist, attenuates pain with reduced toleranceBritish Journal of Pharmacology, 2010
- Bi- or multifunctional opioid peptide drugsLife Sciences, 2010
- The biological activity and metabolic stability of peptidic bifunctional compounds that are opioid receptor agonists and neurokinin-1 receptor antagonists with a cystine moietyBioorganic & Medicinal Chemistry, 2009
- Multiple ligands in opioid research.Protein & Peptide Letters, 2008
- Opioid Complications and Side EffectsPain Physician, 2008
- OpioidsHandbook of Experimental Pharmacology, 2006
- Designed Multiple Ligands. An Emerging Drug Discovery ParadigmJournal of Medicinal Chemistry, 2005
- Opioid ReceptorsAnnual Review of Biochemistry, 2004
- A substance P-opioid chimeric peptide as a unique nontolerance-forming analgesicProceedings of the National Academy of Sciences of the United States of America, 2000