Abstract

The Luteinizing Hormone Receptor (LHR) is a critical G protein-coupled receptor (GPCR) that plays a central role in reproductive physiology, and its pharmacological modulation is essential for treating various hormone-dependent disorders. While peptide-based antagonists exist, the development of orally bioavailable, low-molecular-weight (LMW) antagonists remains a significant therapeutic goal. This study aimed to identify and characterize novel LMW compounds capable of binding to the LHR and exhibiting antagonistic activity. Through a combination of in silico screening and in vitro functional assays, a series of non-steroidal, LMW ligands were discovered and synthesized. Key findings demonstrate that these compounds effectively compete with the native hormone for binding to the LHR, and subsequent cell-based assays confirmed their potent inhibitory effect on LHR-mediated signaling, specifically the suppression of cyclic AMP production. Structure-activity relationship analysis provided insights into the molecular determinants necessary for high-affinity binding and antagonistic function. These novel LMW antagonists represent promising lead compounds for the development of new, non-peptide therapeutics to manage conditions such as precocious puberty, endometriosis, and hormone-sensitive cancers, offering advantages in terms of pharmacokinetics and patient compliance over existing peptide therapies.