In vitro study demonstrates biased signaling and ligand-selective antagonism using benzotriazepin-2-one mimics, indicating distinct pathways for dissecting urotensin receptor pharmacology.
Urotensin II receptor (UT) modulators that differentiate the effects of the endogenous cyclic peptide ligands urotensin II (UII) and urotensin II-related peptide (URP) offer potential for dissecting their respective biological roles in disease etiology. Selective modulators of h UII and URP activities were obtained using 1,3,4-benzotriazepin-2-one mimics of a purported bioactive γ-turn conformation about the Bip-Lys-Tyr tripeptide sequence of urocontrin ([Bip 4 ]URP). Considering an active β-turn conformer about the shared Phe-Trp-Lys-Tyr sequence of UII and URP, 8-substituted 1,3,4-benzotriazepin-2-ones were designed to mimic the Phe-Bip-Lys-Tyr tetrapeptide sequence of urocontrin, synthesized, and examined for biological activity. Subtle 5- and 8-position modifications resulted in biased signaling and selective modulation of h UII- or URP-induced vasoconstriction. For example, p -hydroxyphenethyl analogs 17b – d were strong Gα 13 and βarr1 activators devoid of Gα q -mediated signaling. Tertiary amides 15d and 17d negatively modulated h UII-induced vasoconstriction without affecting URP-mediated responses. Benzotriazepinone carboxamides proved to be exceptional tools for elucidating the pharmacological complexity of UT.
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Wei et al. (2023) studied this question.
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