Glucagonreceptorantagonist I is a competitive antagonist of the glucagonreceptor (GCGR; IC50 = 181 nM). It blocks glucagon-induced glycogenolysis in primary human hepatocytes and isolated liver. Glucagonreceptorantagonist I, at 50 mg/kg, reduces the increase in glucose levels observed after intraperitoneal administration of glucagon in humanized mice. Glucagonreceptorantagonist inactive control does not prevent glucagon-mediated actions.