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.