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 ([Bip]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 C 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.

A [4+3] Cycloaddition Reaction of Aza-ortho-quinone Methides with C,N-Cyclic Azomethine Imines for Synthesis of 1,2,4-Triazepines

“…At this time, the solvent was removed under reduced pressure and the crude product was purified by flash column chromatography to provide cycloadduct 1,2,4-triazepines 3. (24) 8,14-ditosyl-8,9,14,14a-tetrahydrobenzo [5,6] 58, 145.73, 144.65, 138.63, 136.36, 133.81, 133.70, 132.64, 132.31, 131.76, 130.83, 130.59, 130.43, 130.41, 130.39, 128.40, 127.87, 127.37, 127.34, 125.68, 122.25, 72.49, 52.43, 21.53, 21.…”

New directions for urotensin II receptor ligands

“…So far, none of the UT antagonists has been investigated for their ability to also block URP‐mediated function. However, recently developed peptidic and non‐peptidic UT antagonists have demonstrated a wide range of activity against UII‐ and URP‐mediated function . For instance, R‐4a (Figure ) inhibited completely hUII‐induced contractions but increased tremendously URP‐associated vasoconstriction .…”

“…In spite of this promise, clinical studies of UT antagonist candidates, such as ACT‐058362 (Palosuran, Figure ), GSK1440115 (Figure ), and SB‐657510 (Figure ), which in animal models, protected respectively against renal ischemia, diabetic nephropathy, asthma, liver fibrosis, and pulmonary hypertension, most have had limited success due to lack of efficacy in humans . A possible explanation for these disappointments could come from the recently reported UII and URP functional selectivity as well as the ability of some UT antagonists to exert a probe‐dependent effect on those two endogenous ligands . Indeed, altered UT signaling in response to UII or URP can lead to distinct role for each peptide in the pathogenesis and progression of UT‐associated diseases.…”

“…For instance, R‐4a (Figure ) inhibited completely hUII‐induced contractions but increased tremendously URP‐associated vasoconstriction . Recently, it was observed that C 5 p ‐hydroxyphenethenyl benzotriazepin‐2‐one (20g) decreased hUII potency and efficacy without changing URP induced vasoconstriction while its saturated phenethyl counterpart 23g decreased URP potency without influencing hUII‐mediated contraction . Finally, Palosuran, the first non‐peptidic UT antagonist ever described, is able to abolish reduction in perfusion pressure (PP) induced by UII but had no influence on reduction in PP induced by URP .…”

Membrane-tethered peptides derived from intracellular loops 2 and 3 of the urotensin II receptor act as allosteric biased ligands

“…Contingent on their interactions with UT, UII and URP probably induce distinct UT conformational and dynamic changes that lead to divergent signaling profiles with both common and distinct biological activities (2,(17)(18)(19)(20)(21). Recent years have witnessed the emergence of useful molecules, with probe-dependent actions, that could shed light on the respective roles and importance of UII and URP under normal and pathological conditions (13,17,18,(22)(23)(24)(25)(26)(27).…”