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Structure-Activity Relationships of a Novel Cyclic Hexapeptide That Exhibits Multifunctional Opioid Agonism and Produces Potent Antinociceptive Activity.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2024 Jan 11; Vol. 67 (1), pp. 272-288. Date of Electronic Publication: 2023 Dec 20. - Publication Year :
- 2024
-
Abstract
- The cyclic peptide c[d-Lys <superscript>2</superscript> , Asp <superscript>5</superscript> ]-DN-9 has recently been identified as a multifunctional opioid/neuropeptide FF receptor agonist, displaying potent analgesic activity with reduced side effects. This study utilized Tyr-c[d-Lys-Gly-Phe-Asp]-d-Pro-NH <subscript>2</subscript> ( 0 ), a cyclic hexapeptide derived from the opioid pharmacophore of c[d-Lys <superscript>2</superscript> , Asp <superscript>5</superscript> ]-DN-9, as a chemical template. We designed, synthesized, and characterized 22 analogs of 0 with a single amino acid substitution to investigate its structure-activity relationship. Most of these cyclic hexapeptide analogs exhibited multifunctional activity at μ and δ opioid receptors (MOR and DOR, respectively) and produced antinociceptive effects following subcutaneous administration. The lead compound analog 15 showed potent agonistic activities at the MOR, κ opioid receptor (KOR), and DOR in vitro and produced a strong and long-lasting analgesic effect through peripheral MOR and KOR in the tail-flick test. Further biological evaluation identified that analog 15 did not cause significant side effects such as tolerance, withdrawal, or reward liability.
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 67
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38118143
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.3c01347