# Therapeutic potentials of nonpeptidic V2R agonists for partial cNDI-causing V2R mutants

## TL;DR

This study explores nonpeptide V2R agonists as potential treatments for partial congenital nephrogenic diabetes insipidus by restoring impaired receptor function.

## Contribution

The study identifies nonpeptidic V2R agonists that functionally restore partial cNDI-causing V2R mutants with functional selectivity.

## Key findings

- OPC5-related agonists induced prolonged Gs-cAMP signaling without β-arrestin1/2 recruitment in partial V2R mutants.
- Several agonists showed higher cAMP responses than AVP in V2R mutants after prolonged stimulation.
- Docking analysis linked agonist interactions with TM7 coordination to functional selectivity.

## Abstract

Loss-of-function mutations in the type 2 vasopressin receptor (V2R) are a major cause of congenital nephrogenic diabetes insipidus (cNDI). In the context of partial cNDI, the response to desmopressin (dDAVP) is partially, but not entirely, diminished. For those with the partial cNDI, restoration of V2R function would offer a prospective therapeutic approach. In this study, we revealed that OPC-51803 (OPC5) and its structurally related V2R agonists could functionally restore V2R mutants causing partial cNDI by inducing prolonged signal activation. The OPC5-related agonists exhibited functional selectivity by inducing signaling through the Gs-cAMP pathway while not recruiting β-arrestin1/2. We found that six cNDI-related V2R partial mutants (V882.53M, Y1283.41S, L1614.47P, T2736.37M, S3298.47R and S3338.51del) displayed varying degrees of plasma membrane expression levels and exhibited moderately impaired signaling function. Several OPC5-related agonists induced higher cAMP responses than AVP at V2R mutants after prolonged agonist stimulation, suggesting their potential effectiveness in compensating impaired V2R-mediated function. Furthermore, docking analysis revealed that the differential interaction of agonists with L3127.40 caused altered coordination of TM7, potentially contributing to the functional selectivity of signaling. These findings suggest that nonpeptide V2R agonists could hold promise as potential drug candidates for addressing partial cNDI.