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

Abstract

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.

What We Observe In Vivo Is Not Always What We See In Vitro: Development and Validation of 11C-JNJ-42491293, A Novel Radioligand for mGluR2

“…Ritanserin failed to produce any change in radiotracer regional uptake (Supplemental Fig. 1; supplemental materials are available at http://jnm.snmjournals.org), indicating no shared affinity of 11 C-JNJ-42491293 for the 5HT 2A receptor, unlike another mGluR2 PAM compound (27). Kinetic Modeling.…”

Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors

“…Additionally, a pair of back-to-back publications provided further detailed descriptions of its pharmacological and PK properties 279 and preclinical evaluation in antipsychotic models. 280 Not surprisingly, JNJ-40411813 ( 11 ) has a generally attractive preclinical profile, including efficacy similar to that of mGlu 2/3 agonist LY404039 ( 47 ) in multiple antipsychotic animal models. JNJ-40411813 ( 11 ) was also recently examined in a phase II proof-of-concept study in patients with major depressive disorder (MDD) with significant anxiety symptoms.…”

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

“…JNJ‐40411813 and JNJ‐42153605 have been shown to inhibit rapid eye movement sleep and promote positive sleep behaviors such as sleep continuity and efficacy in rodents . JNJ‐40411813, JNJ‐42153605, and LY404039 have been examined previously for potential antipsychotic activity . Therefore, the studies described herein further extend the preclinical profile and potential clinical utility of mGlu 2 ‐acting compounds.…”

“…Because antiseizure drugs are often used in combination, we investigated whether a combination of LEV and the mGlu 2 compounds would significantly affect the dose–response relationship of LEV in the 6 Hz model. JNJ‐40411813 and JNJ‐42153605 have been shown to inhibit rapid eye movement sleep and promote positive sleep behaviors such as sleep continuity and efficacy in rodents . JNJ‐40411813, JNJ‐42153605, and LY404039 have been examined previously for potential antipsychotic activity .…”