title: Mechanism based neurotoxicity of mGlu5 positive allosteric modulators--development challenges for a promising novel antipsychotic target.
abstract: Previous work has suggested that activation of mGlu5 receptor augments NMDA receptor function and thereby may constitute a rational approach addressing glutamate hypofunction in schizophrenia and a target for novel antipsychotic drug development. Here, we report the in vitro activity, in vivo efficacy and safety profile of 5PAM523 (4-Fluorophenyl){(2R,5S)-5-[5-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-3-yl]-2-methylpiperidin-1-yl}methanone), a structurally novel positive allosteric modulator selective of mGlu5. In cells expressing human mGlu5 receptor, 5PAM523 potentiated threshold responses to glutamate in fluorometric calcium assays, but does not have any intrinsic agonist activity. 5PAM523 acts as an allosteric modulator as suggested by the binding studies showing that 5PAM523 did not displace the binding of the orthosteric ligand quisqualic acid, but did partially compete with the negative allosteric modulator, MPyEP. In vivo, 5PAM523 reversed amphetamine-induced locomotor activity in rats. Therefore, both the in vitro and in vivo data demonstrate that 5PAM523 acts as a selective mGlu5 PAM and exhibits anti-psychotic like activity. To study the potential for adverse effects and particularly neurotoxicity, brain histopathological exams were performed in rats treated for 4 days with 5PAM523 or vehicle. The brain exam revealed moderate to severe neuronal necrosis in the rats treated with the doses of 30 and 50 mg/kg, particularly in the auditory cortex and hippocampus. To investigate whether this neurotoxicity is mechanism specific to 5PAM523, similar safety studies were carried out with three other structurally distinct selective mGlu5 PAMs. Results revealed a comparable pattern of neuronal cell death. Finally, 5PAM523 was tested in mGlu5 knock-out (KO) and wild type (WT) mice. mGlu5 WT mice treated with 5PAM523 for 4 days at 100 mg/kg presented significant neuronal death in the auditory cortex and hippocampus. Conversely, mGlu5 KO mice did not show any neuronal loss by histopathology, suggesting that enhancement of mGlu5 function is responsible for the toxicity of 5PAM523. This study reveals for the first time that augmentation of mGlu5 function with selective allosteric modulators results in neurotoxicity.
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA. Electronic address: sophie_parmentier_batteur@merck.com.
authors.forename: Sophie
authors.initials: S
authors.lastname: Parmentier-Batteur
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Hutson
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA.
authors.forename: Karsten
authors.initials: K
authors.lastname: Menzel
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Uslaner
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA.
authors.forename: Britta A
authors.initials: BA
authors.lastname: Mattson
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: O'Brien
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Magliaro
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Forest
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Stump
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Tynebor
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA.
authors.forename: Neville J
authors.initials: NJ
authors.lastname: Anthony
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Tucker
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA.
authors.forename: Xu-Fang
authors.initials: XF
authors.lastname: Zhang
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Gomez
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Huszar
authors.affiliation: Addex Therapeutics, 12, chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lambeng
authors.affiliation: Addex Therapeutics, 12, chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Fauré
authors.affiliation: Addex Therapeutics, 12, chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland.
authors.forename: Emannuel
authors.initials: E
authors.lastname: Le Poul
authors.affiliation: Addex Therapeutics, 12, chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Poli
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Rosahl
authors.affiliation: Addex Therapeutics, 12, chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Rocher
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Hargreaves
authors.affiliation: Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486-0004, USA.
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Williams
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D001549:Benzamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D016466:CHO Cells; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003412:Cricetulus; D018683:Excitatory Amino Acid Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D006801:Humans; D008297:Male; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009336:Necrosis / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D020258:Neurotoxicity Syndromes / Q000473:pathology / Q000503:physiopathology; D010069:Oxadiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics / Q000378:metabolism*
chemical_list: C000594260:(4-fluorophenyl)((5-(5-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-3-yl)-2-methylpiperidin-1-yl)methanone; D014150:Antipsychotic Agents; D001549:Benzamides; D018683:Excitatory Amino Acid Agents; D010069:Oxadiazoles; D064529:Receptor, Metabotropic Glutamate 5
keywords: Antipsychotic activity; Metabotropic glutamate receptor; Neurotoxicity; Positive allosteric modulator; Schizophrenia