2-Oxopiperazine-based gamma-turn conformationally constrained peptides: synthesis of CCK-4 analogues.
2-Oxopiperazine derivatives 1 have been designed as mimetics of gamma-turn conformationally constrained tripeptides. The synthetic pathway devised for the preparation of both epimers of 1 at C(5) involves a reductive amination of cyanomethyleneamino pseudopeptides with amino acid derivatives, followed by regiospecific lactamization of the resulting C-backbone branched pseudopeptides. The versatility of this methodology is illustrated in the synthesis of analogues of the tetrapeptides Boc-[Nle(31)]-CCK-4 and Boc-[Lys(o-tolylaminocarbonyl)(31)]-CCK-4. The introduction of the new conformational restriction into these Boc-CCK-4 analogues led to a loss of 2 or 3 orders of magnitude in the affinity at CCK receptors. These results suggest the absence of a gamma-turn in the bioactive conformation of the C-terminal tripeptide of CCK-4.
Herrero
Susana
S
Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
García-López
M Teresa
MT
Latorre
Miriam
M
Cenarruzabeitia
Edurne
E
Del Río
Joaquín
J
Herranz
Rosario
R
D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D019906:Nuclear Magnetic Resonance, Biomolecular; D010179:Pancreas / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000378:metabolism; D013758:Tetragastrin / Q000031:analogs & derivatives* / Q000378:metabolism
D010455:Peptides; D010879:Piperazines; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D013758:Tetragastrin