3D-QSAR CoMFA study of benzoxazepine derivatives as mGluR5 positive allosteric modulators (original) (raw)
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Preclinical profile of a novel metabotropic glutamate receptor 5 positive allosteric modulator
European Journal of Pharmacology, 2011
Recent reports have indicated that patients with schizophrenia have a profound hypo-functionality of glutamatergic signaling pathways. Positive allosteric modulation of mGlu 5 receptor has been postulated to augment NMDA function and thereby alleviate the glutamatergic hypo-function observed in schizophrenic patients. Here we report the in vitro and in vivo characterization of CPPZ (1-(4-(2-chloro-4-fluorophenyl) piperazin-1-yl)-2-(pyridin-4-ylmethoxy)ethanone), a structurally novel positive allosteric modulator selective for mGlu 5 receptor. In HEK293 cells stably over-expressing human mGlu 5 receptor, CPPZ potentiates the intracellular calcium response elicited by a suboptimal concentration of the endogenous agonist glutamate. CPPZ does not have any intrinsic agonist activity and behaves functionally as a positive allosteric modulator. This is further supported by binding data, which demonstrate that CPPZ is able to displace the negative allosteric modulator MPEP but does not compete with the orthosteric ligand quisqualic acid. Instead, CPPZ enhances the binding of the orthosteric ligand. In native preparations, CPPZ potentiates calcium flux in rat cortical neurons stimulated with the group I agonist dihydroxyphenylglycine (DHPG). In addition, CPPZ modulates long-term potentiation in rat hippocampal slices, a process known to be NMDA dependent. In vivo, CPPZ reverses hyper locomotion triggered by the NMDA open channel blocker MK801 in CD1 mice. CPPZ was also able to reduce rat conditioned avoidance responding to electric shock. Both in vitro and in vivo data demonstrate that this novel compound acts as an mGlu 5 receptor positive allosteric modulator, which modulates NMDA dependent responses and suggests that the enhancement of mGlu 5 receptor activity may prove useful in the treatment of schizophrenia.
Molecular pharmacology, 2010
Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenylethynyl)-pyridine (MPEP) binding site. VU0285683 had anxioly...
Discovery of novel positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5)
Bioorganic & Medicinal Chemistry Letters, 2011
Keywords: mGlu5 Metabotropic glutamate receptor 5 Glutamate NMDAr N-Methyl-D-aspartate receptor Positive allosteric modulator Schizophrenia a b s t r a c t Novel in vitro mGlu 5 positive allosteric modulators with good potency, solubility, and low lipophilicity are described. Compounds were identified which did not rely on the phenylacetylene and carbonyl functionalities previously observed to be required for in vitro activity. Investigation of the allosteric binding requirements of a series of dihydroquinolinone analogs led to phenylacetylene azachromanone 4 (EC 50 11.5 nM). Because of risks associated with potential metabolic and toxicological liabilities of the phenylacetylene, this moiety was successfully replaced with a phenoxymethyl group (27; EC 50 156.3 nM). Derivation of a second-generation of mGlu 5 PAMs lacking a ketone carbonyl resulted in azaindoline (33), azabenzimidazole (36), and N-methyl 8-azaoxazine (39) phenylacetylenes. By scoping nitrogen substituents and phenylacetylene replacements in 39, we identified phenoxymethyl 8-azaoxazine 47 (EC 50 50.1 nM) as a potent and soluble mGlu 5 PAM devoid of both undesirable phenylacetylene and carbonyl functionalities.
ACS Medicinal Chemistry Letters, 2015
Herein, we report the structure−activity relationship of a novel series of (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanones as potent, selective, and orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu 5) positive allosteric modulators (PAMs). On the basis of its robust in vitro potency and in vivo efficacy in multiple preclinical models of multiple domains of schizophrenia, coupled with a good DMPK profile and an acceptable therapeutic window, 17a (VU0409551/JNJ-46778212) was selected as a candidate for further development.
Metabotropic glutamate receptors as therapeutic targets for schizophrenia
Neuropharmacology, 2012
Treatment options for schizophrenia that address all symptom categories (positive, negative, and cognitive) are lacking in current therapies for this disorder. Compounds targeting the metabotropic glutamate (mGlu) receptors hold promise as a more comprehensive therapeutic alternative to typical and atypical antipsychotics and may avoid the occurrence of extrapyramidal side effects that accompany these treatments. Activation of the group II mGlu receptors (mGlu 2 and mGlu 3 ) and the group I mGlu 5 are hypothesized to normalize the disruption of thalamocortical glutamatergic circuitry that results in abnormal glutamaterigic signaling in the prefrontal cortex (PFC). Agonists of mGlu 2 and mGlu 3 have demonstrated efficacy for the positive symptom group in both animal models and clinical trials with mGlu 2 being the subtype most likely responsible for the therapeutic effect. Limitations in the chemical space tolerated by the orthosteric site of the mGlu receptors has led to the pursuit of compounds that potentiate the receptor's response to glutamate by acting at less highly conserved allosteric sites. Several series of selective positive allosteric modulators (PAMs) for mGlu 2 and mGlu 5 have demonstrated efficacy in animal models used for the evaluation of antipsychotic agents. In addition, evidence from animal studies indicates that mGlu 5 PAMs hold promise for the treatment of cognitive deficits that occur in schizophrenia. Hopefully, further optimization of allosteric modulators of mGlu receptors will yield clinical candidates that will allow full evaluation of the potential efficacy of these compounds in the treatment of multiple symptom domains in schizophrenia patients in the near future.
Albert/Pharmacological Schizophrenia, 2012
ABSTRACT This chapter contains sections titled: IntroductionMetabotropic Glutamate Receptors 2 and 3: Structure, Function, and LocalizationStructure–Activity Relationships for Orthosteric MGLU2 and MGLU3 Receptor AgonistsStructure–Activity Relationships for Positive Allosteric Modulators (PAMS) of MGLU2 ReceptorsElectrophysiological Properties of Orthosteric MGLU2 AND MGLU3 Receptor AgonistsElectrophysiological Properties of MGLU2 Receptor Positive Allosteric ModulatorsNeurochemical Effects of Orthosteric MGLU2 and MGLU3 AgonistsBehavioral Pharmacology of Orthosteric MGLU2 and MGLU3 AgonistsBehavioral Pharmacology of MGLU2 Receptor Positive Allosteric ModulatorsClinical Aspects of Orthosteric MGLU2 and MGLU3 Receptor AgonistsSummary and Conclusions References