Introduction and Objective: Gastrointestinal tolerability is a key consideration for weight loss therapies targeting appetite-regulating pathways. Conditioned taste avoidance (CTA) in rodents is a widely used preclinical model to evaluate the potential of compounds to produce nausea and gastrointestinal discomfort. We compared food intake inhibition and CTA responses induced by a small molecule amylin receptor agonist, ACCG-2728, with those of amylin and GLP-1-based peptide agents in lean rats.Methods: Lean rats were intraperitoneally or subcutaneously administered various weight-loss compounds, including ACCG-2728 and multiple peptide amylin or GLP-1 receptor agonists. Food intake was measured following dosing, and CTA responses were assessed using a two-bottle preference paradigm. Dose-response relationships were used to derive ED50 values for food intake inhibition and CTA, and comparative analyses were conducted across tested compounds.Results: CTA studies revealed distinct nausea-like behavioral profiles across weight loss compounds. Comparative analysis demonstrated different relationships between the potency of anorectic efficacy and CTA induction. Semaglutide showed a higher potency on CTA induction than food intake inhibition, while cagrilintide and petrelintide showed comparable potency on both behaviors. ACCG-2728 exhibited a CTA profile in lean rats comparable to that of the amylin peptide cagrilintide and distinct from semaglutide.Conclusion: These data demonstrate that CTA in lean rats can be used to differentiate nausea-like behavioral profiles among weight loss compounds. The small molecule amylin receptor agonist ACCG-2728 showed a comparable CTA profile to cagrilintide in this preclinical model.
X. Fang: Employee; Current; Structure Therapeutics. W. Liang: None. Z. Wang: Employee; Current; Structure Therapeutics. L. Lai: None. H. Zhang: None. F. Zhang: Stock/Shareholder; Current; Eli Lilly and Company, Novo Nordisk A/S.
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