PT  - JOURNAL ARTICLE
AU  - Mikhail Kalinichev
AU  - Melanie Rouillier
AU  - Francoise Girard
AU  - Isabelle Royer-Urios
AU  - Bruno Bournique
AU  - Terry Finn
AU  - Delphine Charvin
AU  - Brice Campo
AU  - Emmanuel Le Poul
AU  - Vincent Mutel
AU  - Sonia Poli
AU  - Stuart A neale
AU  - Thomas E Salt
AU  - Robert Lutjens
TI  - ADX71743, a potent and selective negative allosteric modulator of metabotropic glutamate receptor 7 (mGlu7): in vitro and in vivo characterization
AID  - 10.1124/jpet.112.200915
DP  - 2012 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.112.200915
4099  - http://jpet.aspetjournals.org/content/early/2012/12/20/jpet.112.200915.short
4100  - http://jpet.aspetjournals.org/content/early/2012/12/20/jpet.112.200915.full
AB  - Metabotropic glutamate receptor 7 (mGlu7) has been suggested to be a promising novel target for treatment of a range of disorders including anxiety, PTSD, depression, drug abuse and schizophrenia. In this study we characterized a potent and selective mGlu7 negative allosteric modulator (NAM) ADX71743. In vitro, Schild plot analysis and reversibility test at the target confirmed the NAM properties of the compound and attenuation of L-AP4-induced synaptic depression confirmed activity at the native receptor. The pharmacokinetic analysis of ADX71743 in mice revealed that it is bioavailable following subcutaneous administration and brain-penetrant (CSF concentration/total plasma concentration ratio = 0.8%). In vivo, ADX71743 (50, 100, 150 mg/kg s.c.) caused no impairment of locomotor activity in rats and mice and activity on rotarod in mice. ADX71743 had an anxiolytic-like profile in the marble burying and elevated plus maze tests, dose-dependently reducing the number of buried marbles and increasing open-arm exploration, respectively. While ADX71743 caused a small reduction in amphetamine-induced hyperactivity in mice, it was inactive in the mouse DOI-induced head twitch and the rat conditioned avoidance response tests. Also, the compound was inactive in the mouse forced swim test. These data suggest that ADX71743 is a suitable compound to help unravel the physiological role of mGlu7 and understand better its implication in CNS diseases. Our in vivo tests using ADX71743, reported here, suggest that pharmacological inhibition of mGlu7 is a valid approach for developing novel pharmacotherapies to treat anxiety disorders, but may not be suitable for treatment of depression or psychosis.