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Synthesis and biological properties of new constrained CCK-B antagonists: discrimination of two affinity states of the CCK-B receptor on transfected CHO cells.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 1997 Nov 21; Vol. 40 (24), pp. 3947-56. - Publication Year :
- 1997
-
Abstract
- To improve our knowledge of the bioactive conformation of CCK-B antagonists, we have developed a new series of constrained dipeptoids whose synthesis and biochemical properties are reported here. These compounds, of general structure N alpha-[(2-adamantyloxy)carbonyl]-alpha-methyltryptophanyl-(4 -X)-proline, were designed by introducing a cyclization in the structure of the previously described CCK-B/peptoid antagonist RB 210, N-[N-[(2-adamantyloxy)carbonyl]-DL-alpha-methyltryptophanyl] -N-(2-phenylethyl)glycine (Blommaert et al. J. Med. Chem. 1993, 36, 2868-2877), by means of a five-membered ring. Structure-affinity relationship studies showed that an R configuration of Trp-C alpha and a cis configuration of the pyrrolidine substituents were favorable for receptor recognition. The most potent compounds of this new series had similar affinities for the CCK-B receptor as RB 210 and proved to be far more efficient in inhibiting inositol phosphate production in CHO cells stably transfected with rat brain CCK-B receptor, with IC50 values approaching those of the commonly used antagonists L-365,260 and PD-134,308. Moreover, binding studies performed using transfected CHO cells showed that two affinity states of the CCK-B receptor can be discriminated by some of these compounds which also have different biological profiles and are therefore highly interesting tools for the biochemical and pharmacological characterization of CCK-B receptor heterogeneity.
- Subjects :
- Adamantane chemical synthesis
Adamantane pharmacology
Animals
CHO Cells drug effects
CHO Cells metabolism
CHO Cells ultrastructure
Cricetinae
Guinea Pigs
Kinetics
Magnetic Resonance Spectroscopy
Peptoids
Proline analogs & derivatives
Protein Conformation
Rats
Receptor, Cholecystokinin A
Receptor, Cholecystokinin B
Receptors, Cholecystokinin chemistry
Receptors, Cholecystokinin metabolism
Structure-Activity Relationship
Substrate Specificity
Transfection
Adamantane analogs & derivatives
Dipeptides chemical synthesis
Dipeptides pharmacology
Receptors, Cholecystokinin antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 40
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 9397175
- Full Text :
- https://doi.org/10.1021/jm970439a