LAUSR

ABSTRACT Positive allosteric modulation of the GABAB receptor is a promising alternative to direct activation of the receptor as a therapeutic approach for treatment of addiction, chronic pain, anxiety, epilepsy, autism, Fragile X syndrome, and psychosis. Here we describe in vitro and in vivo characterization of a novel, potent and selective GABAB positive allosteric modulator (PAM) N‐(5‐(4‐(4‐chloro‐3‐fluorobenzyl)‐6‐methoxy‐3,5‐dioxo‐4,5‐dihydro‐1,2,4‐triazin‐2(3H)‐yl)‐2‐fluorophenyl)acetamide (ADX71441). In vitro, Schild plot and reversibility tests at the target confirmed PAM properties of the compound. In mice and rats ADX71441 is bioavailable after oral administration and is brain penetrant. A single dose of ADX71441 had an anxiolytic‐like profile in the mouse marble burying test (minimum effective dose; MED 3 mg/kg) as well as in the elevated plus maze test in mice and rats (both MED 3 mg/kg). Also, in mice, acute administration of ADX71441 reduced visceral pain‐associated behaviors in the acetic acid‐induced writhing test. ADX71441 dose‐dependently reduced time on rotarod in rats (MED 10 mg/kg) indicative of muscle‐relaxant qualities. ADX71441 reduced locomotor activity in mice (10 mg/kg) and rats (3 mg/kg) after single dose; however, following sub‐chronic administration in mice, 30 mg/kg ADX71441 was associated with normal locomotor activity. While acute administration of ADX71441 reduced body temperature in rats and mice (both MED 10 mg/kg), the effect in the former was transient, rapidly returning to normal levels despite high concentrations of the compound remaining in plasma. Thus, the GABAB PAM ADX71441 represents a valid therapeutic approach for development of novel treatment of anxiety, pain and spasticity. HighlightsADX71441 is a novel, potent, selective, orally bioavailable and brain‐penetrant GABAB receptor positive allosteric modulator.In rodents ADX71441 exhibits high bioavailability, long half‐life and large volume of distribution.In vivo, ADX71441 shows anxiolytic‐ and antinociceptive‐like effects with a consistent in vitro/in vivo correlation.