2014
DOI: 10.1016/j.neuropharm.2012.12.003
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Mechanism based neurotoxicity of mGlu5 positive allosteric modulators – Development challenges for a promising novel antipsychotic target

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Cited by 78 publications
(90 citation statements)
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“…Recent reports from our laboratory comparing PAMs with ago-PAMs support the hypothesis that positive allosteric modulators of mGlu 5 that are devoid of intrinsic agonist activity do not carry proconvulsant and epileptogenic side effect liabilities; however, a recent publication describes an mGlu 5 PAM devoid of agonist activity, which nevertheless carried seizurelike adverse effects in rodents Rook et al, 2012;Parmentier-Batteur et al, 2013). The present report highlights the possibility that in vivo biotransformation of mGlu 5 PAMs may result in the CNS exposure of a potent metabolite ligand that bears noticeable switches in pharmacology and/or pharmacokinetic disposition that are distinct from its parent ligand.…”
Section: Discussionmentioning
confidence: 93%
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“…Recent reports from our laboratory comparing PAMs with ago-PAMs support the hypothesis that positive allosteric modulators of mGlu 5 that are devoid of intrinsic agonist activity do not carry proconvulsant and epileptogenic side effect liabilities; however, a recent publication describes an mGlu 5 PAM devoid of agonist activity, which nevertheless carried seizurelike adverse effects in rodents Rook et al, 2012;Parmentier-Batteur et al, 2013). The present report highlights the possibility that in vivo biotransformation of mGlu 5 PAMs may result in the CNS exposure of a potent metabolite ligand that bears noticeable switches in pharmacology and/or pharmacokinetic disposition that are distinct from its parent ligand.…”
Section: Discussionmentioning
confidence: 93%
“…Recent academic and pharmaceutical research accounts of proconvulsant side effects arising from overactivation of mGlu 5 may represent an impediment to the development of mGlu 5 -targeted allosteric modulators for the treatment of schizophrenia Parmentier-Batteur et al, 2013). Recent reports from our laboratory comparing PAMs with ago-PAMs support the hypothesis that positive allosteric modulators of mGlu 5 that are devoid of intrinsic agonist activity do not carry proconvulsant and epileptogenic side effect liabilities; however, a recent publication describes an mGlu 5 PAM devoid of agonist activity, which nevertheless carried seizurelike adverse effects in rodents Rook et al, 2012;Parmentier-Batteur et al, 2013).…”
Section: Discussionmentioning
confidence: 99%
“…6 However, issues remain with potential target-based neurotoxicity and seizure liability due to ago-PAM activity, high fold-shift and/or efficacy, or other unknown mechanisms that have somewhat diminished enthusiasm for this novel mechanism. 9,10 Previous target validation attributed the efficacy of mGlu 5 PAMs, as well as adverse effect liability, to the potentiation of NMDA receptor currents. Emerging data on stimulus bias within allosteric GPCR signaling, however, may offer an approach to potentially mitigate these undesired effects that reduce the therapeutic window and preclude development.…”
mentioning
confidence: 99%
“…About this time, Merck reinitiated an mGlu 5 PAM program through a partnership with Addex Pharmaceuticals and had published a report on mechanism-based toxicity based on data within a series of mGlu 5 PAMs, represented by 5PAM523 ( 25 ). 55 In this study, fluorojade staining showed necrotic neurons in the auditory cortex and hippocampus (Figure 7); moreover, these findings, in part, led Merck to once again abandon their mGlu 5 PAM program. We were aware of this, as well as the potential for neurotoxicity and seizure liabilities (known for group I mGlu agonists) with PAMs that possessed agonist activity, e.g., ago-PAMs.…”
Section: Allosteric Modulation Of Gpcrsmentioning
confidence: 51%