Metabotropic Glutamate Receptor 2 Activators

Abstract

Schizophrenia is a common and severe, often disabling psychiatric illness of unknown aetiology that affects approximately 24 million people worldwide. The illness is characterized by symptomatology comprising positive symptoms (hallucinations and delusional behaviours), negative symptoms (anhedonia, social withdrawal and apathy) and cognitive dysfunction (diminished capacity for learning, memory and executive function). Current pharmacological treatments are effective at alleviating positive symptoms but have limited impact on negative symptoms and cognitive deficits. Furthermore, the extrapyramidal symptoms, hyperprolactinemia and metabolic syndrome, including substantial weight gain, are typical side effects limiting the value of many of these drugs for patients. Thus, drugs that better serve the patient population by effectively treating all symptoms with improved safety and tolerability remain a critical unmet need. Modulation of the metabotropic glutamate type 2 (mGlu2) receptor has emerged as a promising mechanism for the treatment of CNS diseases, with the potential to provide a new and more effective avenue for the treatment of schizophrenia.

Group II Metabotropic Glutamate Receptors as Targets for Novel Antipsychotic Drugs

“…The majority are structurally related to either LY487379 (2,2,2-trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(3-pyridinylmethyl)ethanesulfonamide hydrochloride) or BINA (biphenyl-indanone A), two prototypical mGlu 2 R PAMs ( Conn et al, 2009 ; Niswender and Conn, 2010 ). Many of these compounds are highly selective for mGlu 2 R and do not potentiate responses to activation of mGlu 3 R or any other mGluR subtype ( Cid et al, 2015 ). In addition, group II mGluR negative allosteric modulators (NAMs) have also been developed, but in this case acting at both mGlu 2 R and mGlu 3 R ( Hemstapat et al, 2007 ; Woltering et al, 2008a , b ).…”

Positive allosteric modulators of metabotropic glutamate 2 receptors in schizophrenia treatment

“…This allowed defining BINA’s mechanism of action at the brain circuitry level where its effect was apparent in the prefrontal cortex, caudaute–putamen, nucleus accumbens, and mediodorsal thalamus, structures linked to schizophrenia [109]. After the introduction of LY487379 and BINA, a variety of structurally distinct classes of mGlu 2 R PAMs were discovered, many of which proved to have in vivo activity as well [110]. Early mutagenesis studies identified three amino acid residues in transmembrane (TM) segments IV and V of mGlu 2 R to be critical for the activity of LY487379 and several other mGlu 2 R PAMs [111, 112].…”

Optimization of Novel Aza-benzimidazolone mGluR2 PAMs with Respect to LLE and PK Properties and Mitigation of CYP TDI

“…Positive allosteric modulators (PAMs) offer an alternative approach toward mGluR2 activation with potentially significant advantages over orthosteric agonists . As exemplified by Merck and others , (Figure b), binding to the less homologous 7-transmembrane domain (7-TMD) leads to high subtype selectivity for mGluR2 and thus mitigation of mGluR3-mediated effects. This is significant, as previous studies in mouse models predictive of antipsychotic potential have shown that mGluR2, not mGluR3, mediates the actions of mGlu2/3 receptor dual agonists. , Furthermore, modulation restricts receptor activation only to relevant tissues in the presence of endogenous agonist (glutamate) and reduces the potential for tachyphylaxis, which has been reported with GPCR agonists upon chronic treatment …”

“…With the rat FLIPR EC 50 of 18 measured to be 75 nM, the in vitro – in vivo correlation (IVIVC) was excellent. Furthermore, given the exposure required for full efficacy, 18 stands as one of the most efficacious orally dosed mGluR2 PAM’s to date in a rodent model applicable to clinically proven antipsychotics. − ,,− …”