LY3027788, a diester analog of LY3020371 and an mGlu2/3 receptor antagonist, is a highly potent, orally active prodrug of LY3020371 with notable antidepressant efficacy.

LY3027788 (4.8-27 mg/kg; a single p.o.) significantly decreases immobility times in the forced-swim test, enhances the locomotor stimulant effects of quinpirole at 16 mg/kg in mice, and dose-dependently increases wake time in rats without causing rebound hypersomnolence. It leads to the rapid and dose-proportionate appearance of LY3020371 in plasma of both mice (4.8-27 mg/kg) and rats (3-30 mg/kg). In male Sprague-Dawley mice (20-25 g), a single p.o. dose (4.8, 16, 27 mg/kg; 60 minutes prior to testing) is potent and efficacious with a minimal effective dose of 16 mg/kg in the forced-swim assay and an ED 60 of 8.2 mg/kg.