Opioid receptor binding and in vivo antinociceptive activity of position 3-substituted morphiceptin analogs

Analogs of morphiceptin (Tyr-Pro-Phe-Pro-NH2), a mu-selective opioid receptor ligand, with position 3-modifications, including altered size, lipophilicity, and electronic character, while maintaining aromaticity were synthesized. The activity of the new analogs in in vitro assays and in in vivo hot-plate test of analgesia was compared and the results were consistent. [D-1-Nal(3)]Morphiceptin was the most potent analog of this series with a 26-fold increase in mu-opioid receptor affinity, a 15-fold potency increase in the GPI assay. and a significant potency increase in the hot-plate analgesic test, as compared with morphiceptin. [D-Qal(3)]Morphiceptin was found to be a weak antagonist in the GPI assay. (C) 2004 Elsevier Inc. All rights reserved.