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. 2020 Aug 20;11(9):1717-1722.
doi: 10.1021/acsmedchemlett.0c00223. eCollection 2020 Sep 10.

Insights into the Molecular Determinants Involved in Urocontrin and Urocontrin A Action

Etienne Billard  1 , David Chatenet  1
Affiliations

Insights into the Molecular Determinants Involved in Urocontrin and Urocontrin A Action

Etienne Billard et al. ACS Med Chem Lett. .

Abstract

In the past few years, we have identified two allosteric modulators of the urotensinergic system with probe-dependent action, termed Urocontrin (UC) and Urocontrin A (UCA). Such action is atypical and important since it will allow us to understand the specific function of the functionally selective cognate ligands of this system, namely urotensin II and urotensin II-related peptide. Delineating the molecular determinants involved in this particular behavior would represent an important step toward designing small molecules suitable for pharmacologic and/or therapeutic intervention. Hence, we undertook an exploratory research by replacing the Trp4 residue of URP with several para-substituted phenylalanine amino acids in order to get a grasp on the required nature, distance, and orientation of the side chain of this residue for allosteric modulatory action. We found that the position of the second aromatic group is crucial, and we identified two new allosteric modulators: [Trip4]URP and [Phe(pPy-4)4]URP with probe-dependent action.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Chemical structures of the different nonproteinogenic amino acids introduced at the fourth position in URP.
Figure 2
Figure 2
Representative displacement curves of URP and related analogs using HEK-293-hUT cells and 125I-URP as a radioligand. Data represent the mean ± SEM of at least four independent experiments each performed in duplicate.
Figure 3
Figure 3
Vasoconstrictor effects of URP and related analogs on rat thoracic aorta rings.
Figure 4
Figure 4
Effects of [Trip4]URP (A) or [Phe(pPy-4)4]URP (B) on hUII- (top) or URP-induced contraction (bottom).
Figure 5
Figure 5
Schematic representation of Trip (left) and Pep (right) side-chains. In Trip, ortho-hydrogenes create a sterical barrier that limits the freedom of rotation of the phenyls rings.
Figure 6
Figure 6
Schematic representation of the substituted residue and their neighboring Lys5. In [Phe(pThio-3)4]URP (left) and [Phe(pPy-3)4]URP (center) a H-bond might be expected according to the position of the heteroatom. Such interaction is not permitted in [Phe(pPy-4)4]URP (right).
See this image and copyright information in PMC

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