Pharmacokinetic and pharmacodynamic characterisation of JNJ-40411813, a positive allosteric modulator of mGluR2, in two randomised, double-blind phase-I studies

Salih, Hiba; Anghelescu, Ion; Kezic, I.; Sinha, Vikash; Hoeben, Eef; Nueten, Luc Van; Smedt, Heidi De; Boer, P. de

doi:10.1177/0269881115573403

Cited by 41 publications

(33 citation statements)

References 25 publications

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“…In addition, knowledge of how presynaptic GPCRs such as mGlu 2 modulate circuits that are involved in specific CNS disorders facilitates identification of therapeutic targets. Indeed, agonists and positive allosteric modulators of mGlu 2 have entered clinical trials in recent years for treatment of striatum-related disorders including addiction and schizophrenia (Cross, 2013; Patil et al, 2007; Salih et al, 2015), and enhancing our understanding of how these drugs affect relevant circuits within the context of a particular disorder could facilitate predictions regarding their efficacy for particular symptom-related endpoints.…”

Section: Discussionmentioning

confidence: 99%

Metabotropic glutamate receptor 2 inhibits thalamically-driven glutamate and dopamine release in the dorsal striatum

2017

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The striatum plays critical roles in action control and cognition, and activity of striatal neurons is driven by glutamatergic input. Inhibition of glutamatergic inputs to projection neurons and interneurons of the striatum by presynaptic G protein-coupled receptors (GPCRs) stands to modulate striatal output and striatum-dependent behaviors. Despite knowledge that a substantial number of glutamatergic inputs to striatal neurons originate in the thalamus, most electrophysiological studies assessing GPCR modulation do not differentiate between effects on corticostriatal and thalamostriatal transmission, and synaptic inhibition is frequently assumed to be mediated by activation of GPCRs on corticostriatal terminals. We used optogenetic techniques and recently-discovered pharmacological tools to dissect the effects of a prominent presynaptic GPCR, metabotropic glutamate receptor 2 (mGlu2), on corticostriatal vs. thalamostriatal transmission. We found that an agonist of mGlu2 and mGlu3 induces long-term depression (LTD) at synapses onto MSNs from both the cortex and the thalamus. Thalamostriatal LTD is selectively blocked by an mGlu2-selective negative allosteric modulator and reversed by application of an antagonist following LTD induction. Activation of mGlu2/3 also induces LTD of thalamostriatal transmission in striatal cholinergic interneurons (CINs), and pharmacological activation of mGlu2/3 or selective activation of mGlu2 inhibits CIN-mediated dopamine release evoked by selective stimulation of thalamostriatal inputs. Thus, mGlu2 activation exerts effects on striatal physiology that extend beyond modulation of corticostriatal synapses, and has the potential to influence cognition and striatum-related disorders via inhibition of thalamus-derived glutamate and dopamine release.

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Section: Discussionmentioning

confidence: 99%

Metabotropic glutamate receptor 2 inhibits thalamically-driven glutamate and dopamine release in the dorsal striatum

2017

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“…To date, two mGlu 2 PAMs have progressed to clinical trials: JNJ40411813/ADX71149 [161] and AZD8529 [159]. Phase I assessment in healthy volunteers indicated that JNJ40411813 was generally well tolerated in healthy men and women--with adverse events such as ataxia and somnolence emerging only at high doses [161].…”

Section: Group II Mglu Receptors (Mglu2 and Mglu3)mentioning

confidence: 99%

Targeting metabotropic glutamate receptors for novel treatments of schizophrenia

2017

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Support for the N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia has led to increasing focus on restoring proper glutamatergic signaling as an approach for treatment of this devastating disease. The ability of metabotropic glutamate (mGlu) receptors to modulate glutamatergic neurotransmission has thus attracted considerable attention for the development of novel antipsychotics. Consisting of eight subtypes classified into three groups based on sequence homology, signal transduction, and pharmacology, the mGlu receptors provide a wide range of targets to modulate NMDAR function as well as glutamate release. Recently, allosteric modulators of mGlu receptors have been developed that allow unprecedented selectivity among subtypes, not just groups, facilitating the investigation of the effects of subtype-specific modulation. In preclinical animal models, positive allosteric modulators (PAMs) of the group I mGlu receptor mGlu5 have efficacy across all three symptom domains of schizophrenia (positive, negative, and cognitive). The discovery and development of mGlu5 PAMs that display unique signal bias suggests that efficacy can be retained while avoiding the neurotoxic effects of earlier compounds. Interestingly, mGlu1 negative allosteric modulators (NAMs) appear efficacious in positive symptom models of the disease but are still in early preclinical development. While selective group II mGlu receptor (mGlu2/3) agonists have reached clinical trials but were unsuccessful, specific mGlu2 or mGlu3 receptor targeting still hold great promise. Genetic studies implicated mGlu2 in the antipsychotic effects of group II agonists and mGlu2 PAMs have since entered into clinical trials. Additionally, mGlu3 appears to play an important role in cognition, may confer neuroprotective effects, and thus is a promising target to alleviate cognitive deficits in schizophrenia. Although group III mGlu receptors (mGlu4/6/7/8) have attracted less attention, mGlu4 agonists and PAMs appear to have efficacy across all three symptoms domains in preclinical models. The recent discovery of heterodimers comprising mGlu2 and mGlu4 may explain the efficacy of mGlu4 selective compounds but this remains to be determined. Taken together, compounds targeting mGlu receptors, specifically subtype-selective allosteric modulators, provide a compelling alternative approach to fill the unmet clinical needs for patients with schizophrenia.

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“…Two mGlu 2 PAMs, AZD8529 (AstraZeneca) and JNJ-40411813 (Janssen Pharmaceuticals, Inc., in collaboration with Addex Therapeutics), have been evaluated in small clinical trials (Cross, 2013; Salih et al, 2015). To date, no major safety or tolerability concerns have been reported.…”

Section: Challenges and Progress Towards Novel Pharmacotherapies Formentioning

confidence: 99%

“…To date, no major safety or tolerability concerns have been reported. A small trial assessed the ability of JNJ-40411813 to reduce cigarette craving and smoking in male smokers, and found a trend towards reduced craving but not a reduction of the number of cigarettes smoked (Salih et al, 2015). The U.S. National Institute on Drug Abuse is currently sponsoring a multi-site clinical trial to evaluate AZD8529 for smoking cessation in females (Clinicaltrails.gov identifier: NCT02401022).…”

Section: Challenges and Progress Towards Novel Pharmacotherapies Formentioning

confidence: 99%

Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

Johnson

Lovinger

2016

Front. Cell. Neurosci.

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Drug abuse and addiction cause widespread social and public health problems, and the neurobiology underlying drug actions and drug use and abuse is an area of intensive research. Drugs of abuse alter synaptic transmission, and these actions contribute to acute intoxication as well as the chronic effects of abused substances. Transmission at most mammalian synapses involves neurotransmitter activation of two receptor subtypes, ligand-gated ion channels that mediate fast synaptic responses and G protein-coupled receptors (GPCRs) that have slower neuromodulatory actions. The GPCRs represent a large proportion of neurotransmitter receptors involved in almost all facets of nervous system function. In addition, these receptors are targets for many pharmacotherapeutic agents. Drugs of abuse directly or indirectly affect neuromodulation mediated by GPCRs, with important consequences for intoxication, drug taking and responses to prolonged drug exposure, withdrawal and addiction. Among the GPCRs are several subtypes involved in presynaptic inhibition, most of which are coupled to the Gi/o class of G protein. There is increasing evidence that these presynaptic Gi/o-coupled GPCRs have important roles in the actions of drugs of abuse, as well as behaviors related to these drugs. This topic will be reviewed, with particular emphasis on receptors for three neurotransmitters, Dopamine (DA; D1- and D2-like receptors), Endocannabinoids (eCBs; CB1 receptors) and glutamate (group II metabotropic glutamate (mGlu) receptors). The focus is on recent evidence from laboratory animal models (and some evidence in humans) implicating these receptors in the acute and chronic effects of numerous abused drugs, as well as in the control of drug seeking and taking. The ability of drugs targeting these receptors to modify drug seeking behavior has raised the possibility of using compounds targeting these receptors for addiction pharmacotherapy. This topic is also discussed, with emphasis on development of mGlu2 positive allosteric modulators (PAMs).

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Pharmacokinetic and pharmacodynamic characterisation of JNJ-40411813, a positive allosteric modulator of mGluR2, in two randomised, double-blind phase-I studies

Cited by 41 publications

References 25 publications

Metabotropic glutamate receptor 2 inhibits thalamically-driven glutamate and dopamine release in the dorsal striatum

Metabotropic glutamate receptor 2 inhibits thalamically-driven glutamate and dopamine release in the dorsal striatum

Targeting metabotropic glutamate receptors for novel treatments of schizophrenia

Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

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