title: Preclinical profile of a novel metabotropic glutamate receptor 5 positive allosteric modulator.
abstract: 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.
authors.affiliation: Neuroscience Department, AstraZeneca Pharmaceuticals, Wilmington, DE, United States.
authors.forename: Nathan
authors.initials: N
authors.lastname: Spear
authors.forename: Reto A
authors.initials: RA
authors.lastname: Gadient
authors.forename: Deidre E
authors.initials: DE
authors.lastname: Wilkins
authors.forename: MyLinh
authors.initials: M
authors.lastname: Do
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Smith
authors.forename: Kim L
authors.initials: KL
authors.lastname: Zeller
authors.forename: Patricia
authors.initials: P
authors.lastname: Schroeder
authors.forename: Minli
authors.initials: M
authors.lastname: Zhang
authors.forename: Jalaj
authors.initials: J
authors.lastname: Arora
authors.forename: Vijay
authors.initials: V
authors.lastname: Chhajlani
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001362:Avoidance Learning / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology; D003213:Conditioning, Psychological / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D006168:Guinea Pigs; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D000077489:Piperazine; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: C560864:1-(4-(2-chloro-4-fluorophenyl)piperazin-1-yl)-2-(pyridin-4-ylmethoxy)ethanone; D014150:Antipsychotic Agents; D010879:Piperazines; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D000077489:Piperazine; D016291:Dizocilpine Maleate