Design and synthesis of novel hydrazide-linked bifunctional peptides as delta/mu opioid receptor agonists and CCK-1/CCK-2 receptor antagonists

Journal of Medicinal Chemistry
Yeon Sun LeeVictor J Hruby

Abstract

A series of hydrazide-linked bifunctional peptides designed to act as agonists for delta/mu opioid receptors and antagonists for CCK-1/CCK-2 receptors was prepared and tested for binding to both opioid and CCK receptors and in functional assays. SAR studies in the CCK region examined the structural requirements for the side chain groups at positions 1', 2', and 4' and for the N-terminal protecting group, which are related to interactions not only with CCK, but also with opioid receptors. Most peptide ligands that showed high binding affinities (0.1-10 nM) for both delta and mu opioid receptors generally showed lower binding affinities (micromolar range) at CCK-1 and CCK-2 receptors, but were potent CCK receptor antagonists in the GPI/LMMP assay (up to Ke = 6.5 nM). The results indicate that it is reasonable to design chimeric bifunctional peptide ligands for different G-protein coupled receptors in a single molecule.

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Citations

Mar 20, 2010·Journal of Medicinal Chemistry·Kaleeckal G HarikumarLaurence J Miller
Dec 7, 2010·Journal of Medicinal Chemistry·Yeon Sun LeeVictor J Hruby
Dec 18, 2013·Expert Opinion on Investigational Drugs·Aswini Kumar Giri, Victor J Hruby
Mar 17, 2009·Life Sciences·Peter W Schiller
Nov 14, 2014·Chemical Biology & Drug Design·Adriano MollicaRichard J Lewis
Nov 1, 2016·Journal of Medicinal Chemistry·Cyf N Ramos-ColonVictor J Hruby
Apr 4, 2017·ACS Chemical Neuroscience·Michael RemesicYeon Sun Lee
Jul 28, 2007·Biopolymers·Yeon Sun LeeVictor J Hruby
Nov 7, 2013·Acta Crystallographica. Section C, Crystal Structure Communications·P RajalakshmiMohd Mustaqim Rosli
Aug 1, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jolanta DyniewiczAleksandra Misicka

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