title: In vitro characterisation of the novel positive allosteric modulators of the mGlu₅ receptor, LSN2463359 and LSN2814617, and their effects on sleep architecture and operant responding in the rat.
abstract: The demonstrated functional interaction of metabotropic glutamate 5 (mGlu₅) receptors with N-methyl-d-aspartate (NMDA) receptors has prompted speculation that their activation may offer a potential treatment for aspects of schizophrenia. Development of selective mGlu₅ agonists has been difficult, but several different positive allosteric modulator (PAM) molecules have now been identified. This study describes two novel mGlu₅ PAMs, LSN2463359 (N-(1-methylethyl)-5-(pyridin-4-ylethynyl)pyridine-2-carboxamide) and LSN2814617 [(7S)-3-tert-butyl-7-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-A]pyridine], which are useful tools for this field of research. Both compounds are potent and selective potentiators of human and rat mGlu₅ receptors in vitro, displaying curve shift ratios of two to three fold in the concentration-response relationship to glutamate or the glutamate receptor agonist, DHPG, with no detectable intrinsic agonist properties. Both compounds displaced the mGlu₅ receptor antagonist radioligand, [³H]MPEP in vitro and, following oral administration reached brain concentrations sufficient to occupy hippocampal mGlu₅ receptors as measured in vivo by dose-dependent displacement from the hippocampus of intravenously administered MPEPy. In vivo EEG studies demonstrated that these mGlu₅ PAMs have marked wake-promoting properties but little in the way of rebound hypersomnolence. In contrast, the previously described mGlu₅ PAMs CDPPB and ADX47273 showed relatively poor evidence of in vivo target engagement in either receptor occupancy assays or EEG disturbance. Wake-promoting doses of LSN2463359 and LSN2814617 attenuated deficits in performance induced by the competitive NMDA receptor antagonist SDZ 220,581 in two tests of operant behaviour: the variable interval 30 s task and the DMTP task. These effects were lost if the dose of either compound extended into the range which disrupted performance in the baseline DMTP task. However, the improvements in response accuracy induced by the mGlu₅ potentiators in SDZ 220,581-treated rats were not delay-dependent and, therefore, perhaps more likely reflected optimization of general arousal than specific beneficial effects on discrete cognitive processes. The systematic profiling of LSN2463359 and LSN2814617 alongside other previously described molecules will help determine more precisely how mGlu₅ potentiator pharmacology might provide therapeutic benefit. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
authors.affiliation: Eli Lilly & Company Ltd., Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU20 6PH, United Kingdom. GILMOUR_GARY@LILLY.COM
authors.forename: Gary
authors.initials: G
authors.lastname: Gilmour
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Broad
authors.forename: Keith A
authors.initials: KA
authors.lastname: Wafford
authors.forename: Thomas
authors.initials: T
authors.lastname: Britton
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Colvin
authors.forename: Adam
authors.initials: A
authors.lastname: Fivush
authors.forename: Francois
authors.initials: F
authors.lastname: Gastambide
authors.forename: Brian
authors.initials: B
authors.lastname: Getman
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Heinz
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McCarthy
authors.forename: Lourdes
authors.initials: L
authors.lastname: Prieto
authors.forename: Elaine
authors.initials: E
authors.lastname: Shanks
authors.forename: Janice W
authors.initials: JW
authors.lastname: Smith
authors.forename: Lorena
authors.initials: L
authors.lastname: Taboada
authors.forename: Dale M
authors.initials: DM
authors.lastname: Edgar
authors.forename: Mark D
authors.initials: MD
authors.lastname: Tricklebank
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001143:Arousal / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015507:Drugs, Investigational / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004622:Embryo, Mammalian / Q000166:cytology; D018690:Excitatory Amino Acid Agonists / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018697:Nootropic Agents / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy*; D012894:Sleep Stages / Q000187:drug effects; D014018:Tissue Distribution
chemical_list: D015507:Drugs, Investigational; D018690:Excitatory Amino Acid Agonists; D018697:Nootropic Agents; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins