Boc-Trp-Orn(Z)-Asp-NH2 and derivatives: a new family of CCK antagonists.
The respective roles of the benzyloxycarbonyl group (Z) and of the N-terminal tripeptide moiety in the antagonist properties of the cholecystokinin CCK8 analogue Boc-[Nle28,Orn(Z)31]CCK27-33 (Marseigne et al. J. Med. Chem. 1988, 31, 966.) were studied with the following derivatives: Boc-[Nle28,Orn(X)31]CCK27-33, Boc[Nle28,Orn(X)31]CCK27-32, Boc-[Orn(X)31]CCK30-33, and Boc-[Orn(X)31]CCK30-32 (X = Z, Boc, H). These derivatives, the synthesis of eight of which is reported here, were tested for their abilities to inhibit the binding of [3H]pCCK8 to guinea pig pancreatic and brain membranes and for their potencies in stimulating amylase release from guinea pig pancreatic acini. None of the Z derivatives produced amylase secretion, but they competitively antagonized the stimulation induced by CCK8. The deletion of the N-terminal tripeptide and/or Phe-NH2(33) residue did not play a key role in the recognition of peripheral receptors and in the activity of these peptides, whereas replacement of the Z group by a Boc group slightly decreased the affinities of the compounds for both pancreatic and brain binding sites and their potencies as peripheral antagonists. Moreover, the tetrapeptide Boc-Trp-Orn(Boc)-Asp-Phe-NH2 behaved as a partial agonist and analogues in which the Z or Boc groups on the ornithine residue were removed were full agonists. Interestingly, the short peptide derivative Boc-Trp-Orn(Z)-Asp-NH2 displayed the same affinity (KI = 2.0 +/- 0.2 x 10(-7] and the same antagonist activity (pA2 = 6.63) as its parent compound Boc-[Nle28,Orn(Z)31]CCK27-33. This tripeptide could be an interesting tool for studying the structural relationships between peptide and non-peptide CCK antagonists.
Gonzalez-Muniz
R
R
Département de Chimie Organique, U 266 INSERM, UA 498 CNRS, U.E.R. des Sciences Pharmaceutiques et Biologiques, Paris, France.
Bergeron
F
F
Marseigne
I
I
Durieux
C
C
Roques
B P
BP
D000595:Amino Acid Sequence; D000681:Amylases / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D001681:Biological Assay; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D011949:Receptors, Cholecystokinin / Q000378:metabolism; D012844:Sincalide / Q000031:analogs & derivatives / Q000378:metabolism; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D011949:Receptors, Cholecystokinin; C066620:tert-butyloxycarbonyl-tryptophyl-benzyloxycarbonyl-ornithyl-aspartamide; D002766:Cholecystokinin; D000681:Amylases; D012844:Sincalide