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Novel Asp32-replacement tetrapeptide analogues as potent and selective CCK-A agonists.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 1994 May 27; Vol. 37 (11), pp. 1562-8. - Publication Year :
- 1994
-
Abstract
- A series of novel CCK tetrapeptide analogues of the general formula Boc-Trp-Lys(Tac)-N(R)-(CH2)nCON(R')Phe-NH2 (Tac = o-tolylaminocarbonyl), where R,R' = H or Me and n = 1-5, have been synthesized and tested. These analogues, which lack an acidic residue at the penultimate position, demonstrated surprisingly high CCK-A receptor affinity and selectivity. The effect of N-methylation pattern on CCK-A receptor affinity showed consistent trends for analogues in which n = 1, 2, or 3, with the di-N-methylated analogues having the highest affinity in each case. However, none of these analogues had full agonist activity, as measured by percent maximal PI hydrolysis. Two conformationally constrained analogues also demonstrated high CCK-A receptor affinity and selectivity, as well as nearly maximal agonist activity. In addition, one of these conformationally-constrained analogues demonstrated anorectic activity in rats.
- Subjects :
- Amino Acid Sequence
Animals
Appetite Depressants pharmacology
Cerebral Cortex chemistry
Cholecystokinin chemistry
Guinea Pigs
Methylation
Molecular Sequence Data
Molecular Structure
Oligopeptides metabolism
Oligopeptides pharmacology
Pancreas chemistry
Protein Conformation
Pyrrolidinones metabolism
Pyrrolidinones pharmacology
Rats
Structure-Activity Relationship
Aspartic Acid
Cholecystokinin analogs & derivatives
Oligopeptides chemical synthesis
Pyrrolidinones chemical synthesis
Receptors, Cholecystokinin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 37
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 8201590
- Full Text :
- https://doi.org/10.1021/jm00037a005