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-Nal3]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-Qal3]Morphiceptin was found to be a weak antagonist in the GPI assay.
Fichna
Jakub
J
Department of Medicinal Chemistry, Medical University, Lodz, Poland.
do-Rego
Jean-Claude
JC
Costentin
Jean
J
Chung
Nga N
NN
Schiller
Peter W
PW
Kosson
Piotr
P
Janecka
Anna
A
D000701:Analgesics, Opioid / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D004723:Endorphins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000701:Analgesics, Opioid; D004723:Endorphins; D011957:Receptors, Opioid; C028889:morphiceptin