Cholecystokinin-octapeptide fragments: Binding to brain cholecystokinin receptors

Abstract

Structural determinants of cholecystokinin octapeptide (CCK-8) binding to central nervous system receptors have been studied to assess the relative importance of the amino and the carboxyl end of the active peptide sequence, CCK-(26–33). The relative ability to inhibit equilibrium binding of [ 125I]CCK-33 to guinea pig cortical membranes was determined for a series of amino and carboxyl terminal fragments of CCK-8. While N-acetyl CCK-(26–29), N-acetyl CCK-(26–30) amide and N-acetyl CCK-(26–31) amide were inactive, the N-acetyl CCK-(26–32) amide fragment displayed binding to central receptors. Of the carboxyl terminal peptide fragments, both CCK-(29–33) and CCK-(30–33) bound less potently than CCK-8; CCK-(31–33) interacted more weakly than the tetra- and pentapeptide, but with a higher affinity to brain receptors than to peripheral receptors. The heptapeptide, CCK-(26–32) amide, and the tripeptide, CCK-(31–33), are known to antagonize CCK action at peripheral receptors. The heptapeptide bound to central receptors 25 times more potently than a known peripheral antagonist, dibutyryl cyclic GMP. Thus these peptides may act centrally to oppose CCK-8 mediated functions.