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

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.