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Title

β-Turned dipeptoids as potent and selective CCK1 receptor antagonists

AuthorsMartín-Martínez, Mercedes CSIC ORCID; Figuera, Natalia De la CSIC; Latorre, Miriam; Herranz, Rosario CSIC ORCID; García-López, M. Teresa CSIC ; Cenarruzabeitia, Edurne CSIC; Río, Joaquín del CSIC; González-Muñiz, Rosario CSIC ORCID
KeywordsConformation
Organic acids
Reaction products: Receptors
Selectivity
Issue Date9-Sep-2000
PublisherAmerican Chemical Society
CitationJournal of Medicinal Chemistry 43(20): 3770-3777 (2000)
AbstractTo improve our knowledge of the bioactive conformation of CCK1 antagonists, we previously described that replacement of the α-MeTrp residue of dipeptoids with the (2S,5S,11bR)-2-amino-3-oxohexahydroindolizino[8,7-b]indole-5-carboxylate (IBTM) skeleton, a probed type II‘ β-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]carbamoyl-3-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole, 1a,b, showing high binding affinity and selectivity for CCK1 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 β-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 βHph residues are favorable for CCK1 receptor recognition. Moreover, selectivity for this receptor subtype is critically affected by the β-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 CCK1 receptors, restricted dipeptoid derivative 15a, incorporating the type II‘ IBTM mimetic, shows approximately 6-fold higher CCK1 selectivity than analogue 16a, with the type II mimetic. From these results, we propose that the presence of a β-turn-like conformation within the peptide backbone of dipeptoids could contribute to their bioactive conformation at the CCK1 receptor subtype. Concerning functional activity, compounds 15a and 16a behave as CCK1 receptor antagonists.
Publisher version (URL)http://dx.doi.org/10.1021/jm000959x
URIhttp://hdl.handle.net/10261/337031
DOI10.1021/jm000959x
Identifiersissn: 0022-2623
e-issn: 1520-4804
Appears in Collections:(IQM) Artículos




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