PROGLUMIDE INHIBITS THE DEGRADATION OF CHOLECYSTOKININ OCTAPEPTIDE AND LEUCINEENKEPHALIN BY BRAIN ENZYMES

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Abstract
Proglumide, a derivative of glutaramic acid used in the treatment of ulcers, inhibited the degradation of the C-terminal octapeptide (CCK-8) of cholecystokinin (CCK) by rat brain enzymes. Another antagonist of CCK-gastrin receptors, dibutyryl cGMP had no effect. The effect of proglumide was not specific for CCK peptides since the cleavage of the N-terminal tyrosine residue of Leu-enkephalin by brain enzymes was also inhibited. The inhibition did not involve CCK receptors as it was observed for the degradation of CCK-8 by cytosolic synaptosomal enzymes as well as for the cleavage of the peptide by purified synaptic membranes. The inhibition exerted by proglumide on the degradation of unsulfated CCK-8 by synaptic membranes displayed a non-competitive character with an apparent Ki [inhibition constant] value of 1.3 mM. Two non-competitive Ki values (0.6 and 2.0 mM) were found for the inhibition of the cleavage of Leu-enkephalin. Proglumide inhibited the degradation of CCK-8 by brain enzymes but was ineffective towards the cleavage of this peptide by pancreatic plasma membranes. Comparison of the structure of proglumide with aminopeptidase inhibitors shows some similarities between these molecules and suggests that this compound might act through the same mechanism on brain CCK-8 and Leu-enkaphalin aminopeptidases.