title: ADX71743, a potent and selective negative allosteric modulator of metabotropic glutamate receptor 7: in vitro and in vivo characterization.
abstract: Metabotropic glutamate receptor 7 (mGlu(7)) has been suggested to be a promising novel target for treatment of a range of disorders, including anxiety, post-traumatic stress disorder, depression, drug abuse, and schizophrenia. Here we characterized a potent and selective mGlu(7) negative allosteric modulator (NAM) (+)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d]oxazol-4(5H)-one (ADX71743). In vitro, Schild plot analysis and reversibility tests at the target confirmed the NAM properties of the compound and attenuation of L-(+)-2-amino-4-phosphonobutyric acid-induced synaptic depression confirmed activity at the native receptor. The pharmacokinetic analysis of ADX71743 in mice and rats revealed that it is bioavailable after s.c. administration and is brain penetrant (cerebrospinal fluid concentration/total plasma concentration ratio at C(max) = 5.3%). In vivo, ADX71743 (50, 100, 150 mg/kg, s.c.) caused no impairment of locomotor activity in rats and mice or 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. Whereas ADX71743 caused a small reduction in amphetamine-induced hyperactivity in mice, it was inactive in the mouse 2,5-dimethoxy-4-iodoamphetamine-induced head twitch and the rat conditioned avoidance response tests. In addition, the compound was inactive in the mouse forced swim test. These data suggest that ADX71743 is a suitable compound to help unravel the physiologic role of mGlu(7) and to better understand its implication in central nervous system diseases. Our in vivo tests using ADX71743, reported here, suggest that pharmacological inhibition of mGlu(7) is a valid approach for developing novel pharmacotherapies to treat anxiety disorders, but may not be suitable for treatment of depression or psychosis.
authors.affiliation: Addex Therapeutics SA, 12 Chemin des Aulx, CH-1228, Plan-les-Ouates, Geneva, Switzerland. mikhail.kalinichev@addexpharma.com
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kalinichev
authors.forename: Mélanie
authors.initials: M
authors.lastname: Rouillier
authors.forename: Francoise
authors.initials: F
authors.lastname: Girard
authors.forename: Isabelle
authors.initials: I
authors.lastname: Royer-Urios
authors.forename: Bruno
authors.initials: B
authors.lastname: Bournique
authors.forename: Terry
authors.initials: T
authors.lastname: Finn
authors.forename: Delphine
authors.initials: D
authors.lastname: Charvin
authors.forename: Brice
authors.initials: B
authors.lastname: Campo
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Le Poul
authors.forename: Vincent
authors.initials: V
authors.lastname: Mutel
authors.forename: Sonia
authors.initials: S
authors.lastname: Poli
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Neale
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Salt
authors.forename: Robert
authors.initials: R
authors.lastname: Lütjens
mesh_terms: D000494:Allosteric Regulation; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001008:Anxiety Disorders / Q000188:drug therapy / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D002460:Cell Line; D023902:Chromosome Pairing / Q000187:drug effects; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010081:Oxazolone / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; C102719:metabotropic glutamate receptor 7; D010081:Oxazolone; D000661:Amphetamine