Indole-Containing Amidinohydrazones as Nonpeptide, Dual RXFP3/4 Agonists: Synthesis, Structure–Activity Relationship, and Molecular Modeling Studies

The central relaxin-3/RXFP3 system
plays important roles in stress
responses, feeding, and motivation for reward. However, exploration
of its therapeutic applications has been hampered by the lack of small
molecule ligands and the cross-activation of RXFP1 in the brain and
RXFP4 in the periphery. Herein, we report the first structure–activity
relationship studies of a series of novel nonpeptide amidinohydrazone-based
agonists, which were characterized by RXFP3 functional and radioligand
binding assays. Several potent and efficacious RXFP3 agonists (e.g., 10d) were identified with EC50 values <10 nM.
These compounds also had high potency at RXFP4 but no agonist activity
at RXFP1, demonstrating > 100-fold selectivity for RXFP3/4 over
RXFP1. In vitro ADME and pharmacokinetic assessments
revealed that
the amidinohydrazone derivatives may have limited brain permeability.
Collectively, our findings provide the basis for further optimization
of lead compounds to develop a suitable agonist to probe RXFP3 functions
in the brain.