Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 14, Pages 6075-6086Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00403
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Funding
- NIH [P01-DA006284]
- Univ. of Arizona
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A major limitation in the study of the mu-delta oploid receptor heterodimer (MDOR) is that few selective pharmacological tools exist and no heteromer-selective antagonists. We thus designed a series of variable-length (15-41 atoms) bivalent linked peptides with selective but moderate/low-affinity pharmacophores for the mu and delta opioid receptors. We observed a U-shaped MDOR potency/affinity profile in vitro, with the 24-atom spacer length (D24M) producing the highest MDOR potency/affinity (<1 nM) and selectivity (>= 89-fold). We further evaluated D24M in mice and observed that D24M dose-dependently antagonized tail flick antinociception produced by the MDOR agonists CYM51010 and Deltorphin-II, without antagonizing the monomer agonists DAMGO and DSLET. We also observed that D24M sharply reduced withdrawal behavior
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