In vivo activities of peptide and pseudo-peptide analogs of the C-terminal octapeptide of cholecystokinin on pancreatic secretion in the rat.
Most studies measuring the agonist and antagonist activities of CCK analogs and derivatives on the exocrine pancreas have been done with in vitro models. However, extrapolation to the in vivo situation may be sometimes hazardous, due to the catabolism of the peptides by circulating and tissue peptidases, and to their eventual interaction with various endogenous factors. The present experiments were organized to measure the efficacy and potency on pancreatic secretion of the rat in vivo of a series of CCK 8 analogs whose binding and activity had been previously measured on guinea-pig and rat isolated acini. The molecules tested were derivatives of Boc-(Nle 28-Nle 31)-CCK 26-33 (1), and comprised 2-phenylethylester derivatives, des-Phe derivatives, and a series of pseudo-peptides with a "reduced" bond CH2-NH replacing the peptide bond in position 28-29 to 32-33. They were perfused in anaesthetized rats, and the outputs of sodium, bicarbonate and total protein were measured. All of the derivatives studied had in vivo the same efficacy as (1) on the output of protein, and were 10 to 500 times less potent. For most compounds, the relative order of potencies measured in vivo was similar to that measured in vitro on amylase secretion by rat acini. However, the derivatives with reduced bonds in positions 28-29 and 29-30 were respectively 3 and 2 times less potent in vivo, relative to (1), while derivatives with reduced bonds in positions 30-31, 31-32 and 32-33 were 1.5 to 2.5 times more potent in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
INSERM U 239, Faculté de Médecine X Bichat, Paris, France.
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Nagain
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Rodriguez
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Martinez
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Rozé
D000818:Animals; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012844:Sincalide / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D010446:Peptide Fragments; D012844:Sincalide