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: Mikhail Kalinichev, Mélanie Rouillier, Francoise Girard, Isabelle Royer-Urios, Bruno Bournique, Terry Finn, Delphine Charvin, Brice Campo, Emmanuel Le Poul, Vincent Mutel, Sonia Poli, Stuart A Neale, Thomas E Salt, Robert Lütjens
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 344 Issue 3 Pg. 624-36 (Mar 2013) ISSN: 1521-0103 [Electronic] United States
• PMID: 23257312 (Publication Type: Journal Article)

Chemical References

• Receptors, Metabotropic Glutamate
• Recombinant Proteins
• metabotropic glutamate receptor 7
• Oxazolone
• Amphetamine

Topics

• Allosteric Regulation
• Amphetamine (pharmacology)
• Animals
• Anxiety Disorders (drug therapy, metabolism)
• Behavior, Animal (drug effects)
• Cell Line
• Chromosome Pairing (drug effects)
• Depressive Disorder (drug therapy, metabolism)
• Female
• HEK293 Cells
• Hippocampus (drug effects, metabolism)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Motor Activity (drug effects)
• Oxazolone (pharmacokinetics, pharmacology)
• Protein Binding (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptors, Metabotropic Glutamate (metabolism)
• Recombinant Proteins (pharmacology)