Pharmacological and pharmacokinetic properties of JNJ‐40411813, a positive allosteric modulator of the mGlu2 receptor

Lavreysen, Hilde; Ahnaou, A.; Drinkenburg, W.H.I.M.; Langlois, Xavier; Mackie, Claire; Pype, Stefan; Lütjens, Robert; Poul, Emmanuel Le; Trabanco, Andrés A.; Nuñez, José María Cid

doi:10.1002/prp2.96

Cited by 33 publications

(38 citation statements)

References 34 publications

(42 reference statements)

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“…In these studies, plasma levels of JNJ‐40411813 and LEV do not differ whether they are administered alone or in combination. The levels of JNJ‐40411813 observed at a dose of 10 mg/kg are similar to the EC 50 value (~1,200 ng/ml), obtained from pharmacokinetic–pharmacodynamic modeling based on receptor occupancy studies in rats . Similarity in plasma levels for each of JNJ‐40411813 administered alone or in combination suggests that there are not likely pharmacokinetic effects (i.e., inhibition of metabolism) that contribute to the superior efficacy observed with coadministration of the two compounds.…”

Section: Discussionsupporting

confidence: 66%

Efficacy of mGlu₂‐positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures

et al. 2017

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Section: Discussionsupporting

confidence: 66%

Efficacy of mGlu₂‐positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures

et al. 2017

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“…As ritanserin shows activity in some of these models (PCP‐induced hyperlocomotion, memantine‐induced brain activation and DOM‐induced head twitches), the question remains, however, whether 5HT 2A antagonism contributes to some of the effects observed with JNJ‐40411813. Relatively high doses of JNJ‐42153605 were needed to inhibit DOM‐induced head twitches relative to its ED 50 for mGlu2 occupancy (ED 50 DOM model = 10.7 mg/kg s.c. vs. ED 50 occupancy = 1.1 mg/kg p.o., data not shown, te Riele et al., ), while for JNJ‐40411813, 50% occupancy is reached at a dose between 2.5 and 10 mg/kg s.c. (Lavreysen et al submitted) and the ED 50 for inhibiting DOM effects is “only” 4.7 mg/kg s.c. Hence, while 5HT 2A antagonism may partly mediate JNJ‐40411813's effects against DOM, these effects were likely mediated via the in vivo generation of a metabolite with potent 5HT 2A antagonistic activity.…”

Section: Discussionmentioning

confidence: 99%

“…JNJ‐40411813 (1‐butyl‐3‐chloro‐4‐(4‐phenyl‐1‐piperidinyl)‐2 (1 H )‐pyridinone) is a novel mGlu2 receptor PAM (Lavreysen et al submitted); in vitro, it has a potency of approximately 150 nmol/L and an efficacy or E max of about 270% at the human mGlu2 receptor. In vivo, JNJ‐40411813 not only binds to the mGlu2 receptor (as demonstrated via ex vivo mGlu2 receptor occupancy), but also elicits functional mGlu2‐mediated effects (as shown via sleep‐wake EEG monitoring).…”

Section: Introductionmentioning

confidence: 99%

Preclinical evaluation of the antipsychotic potential of the mGlu2‐positive allosteric modulator JNJ‐40411813

Lavreysen

Langlois

Donck

et al. 2015

Pharmacology Res & Perspec

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JNJ-40411813/ADX71149 (1-butyl-3-chloro-4-(4-phenylpiperidin-1-yl) pyridin-2(1H)-one) is a positive allosteric modulator (PAM) of the mGlu2 receptor, which also displays 5-Hydroxytryptamine (5HT2A) antagonism after administration in rodents due to a rodent-specific metabolite. JNJ-40411813 was compared with the orthosteric mGlu2/3 agonist LY404039 (4-amino-2-thiabicyclo [3.1.0] hexane-4,6-dicarboxylic acid 2,2-dioxide), the selective mGlu2 PAM JNJ-42153605 (3-(cyclopropylmethyl)-7-(4-phenylpiperidin-1-yl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine) and the 5HT2A antagonist ritanserin in rodent models for antipsychotic activity and potential side effects, attempting to differentiate between the various compounds and mechanisms of action. In mice, JNJ-40411813, JNJ-42153605, and LY404039 inhibited spontaneous locomotion and phencyclidine- and scopolamine-induced but not d-amphetamine-induced hyperlocomotion; the 5HT2A antagonist ritanserin inhibited only spontaneous locomotion and phencyclidine-induced hyperlocomotion. As measured by 2-deoxyglucose uptake, all compounds reversed memantine-induced brain activation in mice. The two mGlu2 PAMs and LY404039, but not ritanserin, inhibited conditioned avoidance behavior in rats. Like ritanserin, the mGlu2 ligands antagonized 2,5-dimethoxy-4-methylamphetamine-induced head twitches in rats. LY404039 but not the mGlu2 PAMs impaired rotarod performance in rats and increased the acoustic startle response in mice. Our results show that although 5HT2A antagonism has effect in some models, mGlu2 receptor activation is sufficient for activity in several animal models of antipsychotic activity. The mGlu2 PAMs mimicked the in vivo pharmacodynamic effects observed with LY404039 except for effects on the rotarod and acoustic startle, suggesting that they produce a primary activity profile similar to that of the mGlu2/3 receptor agonist while they can be differentiated based on their secondary activity profile. The results are discussed in light of clinical data available for some of these molecules, in particular JNJ-40411813.

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“…At a dose of 3 mg/kg po, JNJ‐40411813 dose‐dependently suppressed rapid eye movement sleep and promoted and consolidated deep sleep in rats …”

Section: Jnj‐40411813 and Positive Allosteric Modulators Of Glutamatementioning

confidence: 99%

Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). I. Drugs in preclinical and early clinical development

Bialer

Johannessen

Koepp³

et al. 2018

Epilepsia

115

103

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Summary The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain, on May 13‐16, 2018 and was attended by 168 delegates from 28 countries. The conference provided a forum for professionals involved in basic science, clinical research, regulatory affairs, and clinical care to meet and discuss the latest advances related to discovery and development of drugs and devices aimed at improving the management of people with epilepsy. This progress report provides a summary of findings on investigational compounds for which data from preclinical or early (phase I) clinical studies were presented. The compounds reviewed include adenosine and adenosine kinase inhibitors, BIS‐001 (huperzine A), 2‐deoxy‐d‐glucose, FV‐082, FV‐137, JNJ‐40411813, JNJ‐55511118 and analogs, ketone‐enhanced antiepileptic drugs, oxynytones, OV329, TAK‐935 (OV935), XEN901, and XEN1101. Many innovative approaches to drug development were presented. For example, some compounds are being combined with traditional antiepileptic drugs based on evidence of synergism in seizure models, some act as inhibitors of enzymes involved in modulation of neuronal activity, and some interact in novel ways with excitatory receptors or ion channels. Some of the compounds in development target the etiology of specific epilepsy syndromes (including orphan conditions) through precision medicine, and some offer hope of producing disease‐modifying effects rather than symptomatic seizure suppression. Overall, the results summarized in the report indicate that important advances are being made in the effort to develop compounds with potentially improved efficacy and safety profiles compared with existing agents.

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Pharmacological and pharmacokinetic properties of JNJ‐40411813, a positive allosteric modulator of the mGlu2 receptor

Cited by 33 publications

References 34 publications

Efficacy of mGlu₂‐positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures

Efficacy of mGlu₂‐positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures

Preclinical evaluation of the antipsychotic potential of the mGlu2‐positive allosteric modulator JNJ‐40411813

Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). I. Drugs in preclinical and early clinical development

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Pharmacological and pharmacokinetic properties of JNJ‐40411813, a positive allosteric modulator of the mGlu2 receptor

Cited by 33 publications

References 34 publications

Efficacy of mGlu2‐positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures

Efficacy of mGlu2‐positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures

Preclinical evaluation of the antipsychotic potential of the mGlu2‐positive allosteric modulator JNJ‐40411813

Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). I. Drugs in preclinical and early clinical development

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Efficacy of mGlu₂‐positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures

Efficacy of mGlu₂‐positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures