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 hUII 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 ([Bip4]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 hUII- or URP-induced vasoconstriction.
For example, p-hydroxyphenethyl analogs 17b–d were strong Gα13 and βarr1
activators devoid of Gαq-mediated signaling. Tertiary
amides 15d and 17d negatively modulated hUII-induced vasoconstriction without affecting URP-mediated
responses. Benzotriazepinone carboxamides proved to be exceptional
tools for elucidating the pharmacological complexity of UT.