Discovery and Characterization of RGH-122, a Potent, Selective, and Orally Bioavailable V1a Receptor Antagonist

Area of Science:

• Neuroscience
• Pharmacology
• Medicinal Chemistry

Background:

• Arginine-vasopressin (AVP) influences social and emotional behaviors via the V1a receptor.
• The V1a receptor is a potential therapeutic target for neuropsychiatric disorders.

Purpose of the Study:

• To design and synthesize novel, selective V1a receptor antagonists.
• To identify a clinical candidate with improved in vitro and in vivo efficacy.

Main Methods:

• Structure-activity relationship (SAR) studies were conducted for optimization.
• Low nanomolar antagonists were developed through iterative design and synthesis.
• Compound 43 (RGH-122) was identified as a clinical candidate.
• In vivo central nervous system (CNS) activity was assessed using a 3-chamber social preference test in an autism model.

Main Results:

• Novel V1a antagonists with low nanomolar potency were synthesized.
• Compound 43 (RGH-122) demonstrated promising in vitro and in vivo profiles.
• RGH-122 significantly enhanced social preference in the autism model.
• The lowest effective dose for RGH-122 in the social preference test was 1.5 mg/kg.

Conclusions:

• Selective V1a antagonists, including RGH-122, represent a promising therapeutic strategy for neuropsychiatric conditions.
• RGH-122 exhibits potential for treating social deficits associated with autism spectrum disorder.
• Further development of RGH-122 is warranted based on its efficacy in preclinical models.