Analgesic activity of lipotropin C fragment depends on carboxyl terminal tetrapeptide

Abstract

A SERIES of peptides with morphine-like activity has been identified in extracts of pituitary^1–3 and brain^4–7. With the exception of Leu-enkephalin, all those characterised represent some fraction of the 31-residue C fragment—a specific activation product of lipotropin^1,8. Several attempts have been made to define the receptor requirements of opiate peptides^9,10 and to make potent and stable agonists^5,11,12, but essentially all the studies have been based on the easily synthesised NH₂-terminal pentapeptide of C fragment, Met-enkephalin. Unlike the enkephalins, C fragment has a high potency in its central actions^13–16, in vivo and in vitro, and it is relatively stable to brain peptidases^17–19. C fragment is the only naturally occurring peptide to possess strong analgesic properties and have a long lasting action²⁰. It is clear that specific regions of the molecular structure, not present in γ and α endrophin or Met-enkephalin, have a role in the expression of its central activity. We present here evidence that the COOH-terminal tetrapeptide of C fragment, Lys-Lys-Gly-Gln, is responsible for the unique affinity of C fragment for brain opiate receptors and that the presence of all four residues is essential for the high analgesic potency.