Design, Synthesis, and Biological Assessment of Biased Allosteric Modulation of the Urotensin II Receptor Using Achiral 1,3,4-Benzotriazepin-2-one Turn Mimics

Abstract : Benzotriazepin-2-ones were designed to mimic the suggested bioactive γ-turn conformation of the Bip-Lys-Tyr tripeptide in Urocontrin ([Bip4]URP), which modulates the urotensin II receptor (UT) and differentiates the effects of the endogenous ligands urotensin II (UII) and urotensin II-related peptide (URP). Twenty-six benzotriazepin-2-ones were synthesized by acylation of anthranilate-derived amino ketones with an aza-glycine equivalent, chemoselective nitrogen functionalization, and ring closure. Several mimics exhibited selective modulatory effects on hUII- and URP-associated vasoconstriction in an ex vivo rat aortic ring bioassay. The C5 p-hydroxyphenethenyl benzotriazepin-2-one 20g decreased hUII potency and efficacy without changing URP induced vasoconstriction. Its saturated phenethyl counterpart 23g decreased URP potency without influencing hUII-mediated contraction. To our knowledge, 20g and 23g represent the first achiral molecules that modulate selectively hUII and URP biological activities. Effectively synthesized, benzotriaepin-2-one turn mimics offer the potential to differentiate the respective roles, signaling pathways, and phenotypic outcomes of hUII and URP in the UT system.
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https://hal-riip.archives-ouvertes.fr/pasteur-01688987
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Submitted on : Friday, January 19, 2018 - 10:56:50 PM
Last modification on : Monday, October 8, 2018 - 5:44:05 PM

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Antoine Douchez, Étienne Billard, Terence Hébert, David Chatenet, William Lubell. Design, Synthesis, and Biological Assessment of Biased Allosteric Modulation of the Urotensin II Receptor Using Achiral 1,3,4-Benzotriazepin-2-one Turn Mimics. Journal of Medicinal Chemistry, American Chemical Society, 2017, 60 (23), pp.9838 - 9859. ⟨10.1021/acs.jmedchem.7b01525⟩. ⟨pasteur-01688987⟩

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