Enzyme inhibitor
This brain-penetrant mGlu7 allosteric negative modulator (FW = 269.34 g/mol; CAS 1431641-29-0; Solubility: 100 mM in DMSO), also named 6- (2,4-dimethylphenyl)-2-ethyl-6,7-dihydro-4(5H)-benzoxazolone, potently and selectively targets the metabotropic glutamate receptor-7, itself a promising novel target for treatment of anxiety, post-traumatic stress disorder, depression, drug abuse, and schizophrenia. When tested 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 (or L-AP4) -induced synaptic depression confirmed activity at the native receptor. When tested in vitro, ADX-71743 gives a IC50 value versus EC80 of glutamate = 22 nM at human mGlu7 in a 3’,5’- cyclic-AMP assay, with IC50 values versus EC80 of L-AP4 are 63 and 125 nM at human mGlu7 in Ca2+ and cAMP assays respectively; IC50 value versus EC80 of L-AP4 = 88 nM at rmGlu7 in a Ca2+assay). Selective for mGlu7 over all other mGlu receptor subtypes and a panel of relevant GPCRs. Exhibits an anxiolytic-like profile in vivo. The Schild plot experiments clearly indicate the noncompetitive nature of ADX71743 inhibition, whereas simple wash experiments seem to indicate that its binding to the receptor is readily reversible. Other Targets: When tested for its action at other mGlu-expressing cells in series of FLIPR experiments, ADX71743 showed no detectable activity (either agonist or allosteric effects) in cell lines expressing hmGlu3, hmGlu4, rmGlu5, hmGlu6, and hmGlu8. A negligible inhibition of rmGlu1 (32% at 30 μM) and a weak positive allosteric modulator effect on hmGlu2 (EC50 = 11 μM) was measured. When further tested in a functional GPCR screen against 27 targets in agonist and antagonist modes, ADX71743 exhibited no stimulation or inhibition above 27% was observed.
