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image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
Journal of Medicinal Chemistry
Article . 2000 . Peer-reviewed
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β-Turned Dipeptoids as Potent and Selective CCK1 Receptor Antagonists

Authors: Martín-Martínez, Mercedes; Figuera, Natalia De la; Latorre, Miriam; Herranz, Rosario; García-López, M. Teresa; Cenarruzabeitia, Edurne; Río, Joaquín del; +1 Authors

β-Turned Dipeptoids as Potent and Selective CCK1 Receptor Antagonists

Abstract

To improve our knowledge of the bioactive conformation of CCK(1) antagonists, we previously described that replacement of the alpha-MeTrp residue of dipeptoids with the (2S,5S, 11bR)-2-amino-3-oxohexahydroindolizino[8,7-b]indole-5-carbox ylate (IBTM) skeleton, a probed type II' beta-turn mimetic, led to restricted analogues (2S,5S,11bR,1'S)- and (2S,5S,11bR, 1'R)-2-(benzyloxycarbonyl)amino-5-[1'-benzyl-2'-(carboxy)ethyl]carbam oyl-3-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole, 1a,b, showing high binding affinity and selectivity for CCK(1) receptors. In this report, we describe the synthesis and binding profile of new analogues of compounds 1 designed to explore the importance of the C-terminal residue and of the type of beta-turn on the receptor binding affinity and selectivity. Structure-affinity relationship studies show that a C-terminal free carboxylic acid and an S configuration of the Phe and betaHph residues are favorable for CCK(1) receptor recognition. Moreover, selectivity for this receptor subtype is critically affected by the beta-turn type. Thus, while compounds 15a and 16a, containing the (2S,5S,11bR)- and (2R,5R, 11bS)-IBTM frameworks, respectively, are both endowed with nanomolar affinity for CCK(1) receptors, restricted dipeptoid derivative 15a, incorporating the type II' IBTM mimetic, shows approximately 6-fold higher CCK(1) selectivity than analogue 16a, with the type II mimetic. From these results, we propose that the presence of a beta-turn-like conformation within the peptide backbone of dipeptoids could contribute to their bioactive conformation at the CCK(1) receptor subtype. Concerning functional activity, compounds 15a and 16a behave as CCK(1) receptor antagonists.

Keywords

Cerebral Cortex, Indoles, Molecular Mimicry, Indolizines, Molecular Conformation, Stereoisomerism, Dipeptides, In Vitro Techniques, Protein Structure, Secondary, Rats, Radioligand Assay, Organic acids, Animals, Selectivity, Receptors, Cholecystokinin, Conformation, Pancreas, Reaction products: Receptors

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selected citations
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This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
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