Allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2). Part 3: Identification and biological activity of indanone containing mGlu2 receptor potentiators

Pharmacological Characterization of JNJ-40068782, a New Potent, Selective, and Systemically Active Positive Allosteric Modulator of the mGlu2 Receptor and Its Radioligand [3H]JNJ-40068782

“…Minimal efficacy at sufficiently low doses as well as short duration of action, however, limited its use for further development. Pinkerton et al (2005) reported an alternative series of mGlu2 PAMs, of which the prototypic example biphenyl-indanone A (BINA) demonstrates long-lasting activity in some animal models used to predict potential antipsychotic and anxiolytic activity (Galici et al, 2006). Recently, the structurally novel allosteric potentiator N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenxoy)methylbenzyl)-1-methyl-1H-imidazo-4-carboxamide (THIIC; also known as LY2607540), which seems to have activity in models predicting either anxiolytic or antidepressant effects, was reported (Fell et al, 2011).…”

Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 2 (mGluR2)

“…Compound 63 also maintains the favorable brain to plasma ratio of 1.2 that seems to be characteristic of the thio-pyridine series [71]. Utilization of the dichloro indanone group in the thio-pyridine series led to compound 64 which possesses both good potency (EC 50 = 186 nM) and a very high potentiation value of 169% [74]. Compound 64 maintained good brain penetration (brain/plasma = 1.08) and generated a brain concentration of 240 nM 2 h after a 20 mg/kg i.p.…”

“…Removal of the amide linker brought the pharmacokinetic properties of 47 back to the level of 36 and also served to increase potency (47, EC 50 = 223 nM, maximum potentiation = 85%). Incorporation of the butanediol linker had little effect on the EC 50 value for compound 48 (225 nM) but increased the maximum potentiation value to the full potentiator range (97%) [74].…”

“…Compound 46 has an EC 50 of 600 nM and a maximum potentiation value of 86% [74]. This compound is structurally similar to compound 36 but, unlike 36, has very poor bioavailability and high clearance.…”

“…This compound was then studied in the ketamine-induced hyperactivity rat model and showed efficacy at a dose of 40 mg/kg i.p. [74].…”