Urotensin II Receptor Modulation with 1,3,4-Benzotriazepin-2-one Tetrapeptide Mimics.

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.