Cyclic Enkephalins with a Diversely Substituted Guanidine Bridge or a Thiourea Bridge: Synthesis, Biological and Structural Evaluations

Abstract : Two series of 22 and 15 atom cyclic enkephalins incorporating a diversely substituted guanidine bridge have been prepared to assess the potential effect of the bridge substitutions on their opioid activity profile. The most notable results were obtained with the shortest cyclic analogues, which showed a significant variation of their binding affinity toward mu and delta opioid receptors in relation to bridge substitution. NMR studies were performed to rationalize these data. Some small analogues were found to exist as at least one major and one minor stable forms, which could be separated by chromatography. In particular, the compounds 13 and 14 with a cyclic substituent were separated in three isomers and the basis of this multiplicity was explored by 2D NMR spectroscopy. All compounds were agonists with slight selectivity for the mu opioid receptor. Compounds 7a (thiourea bridge) and 10a (N-Me-guanidine bridge) showed nanomolar affinity toward mu receptor, the latter being the more selective for this receptor (40-fold).
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Journal of Medicinal Chemistry, American Chemical Society, 2013, 56 (14), pp.5964-5973. 〈10.1021/jm4008592〉
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Soumis le : mercredi 29 mars 2017 - 16:52:28
Dernière modification le : mardi 24 juillet 2018 - 16:43:05

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Youness Touati-Jallabe, Engin Bojnik, Baptiste Legrand, Elodie Mauchauffee, Nga N. Chung, et al.. Cyclic Enkephalins with a Diversely Substituted Guanidine Bridge or a Thiourea Bridge: Synthesis, Biological and Structural Evaluations. Journal of Medicinal Chemistry, American Chemical Society, 2013, 56 (14), pp.5964-5973. 〈10.1021/jm4008592〉. 〈hal-01498205〉

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