Open AccessPreclinical evaluation of the antipsychotic potential of the mGlu2‐positive allosteric modulator JNJ‐40411813
Author(s) -
Lavreysen Hilde,
Langlois Xavier,
Donck Luc Ver,
Nuñez José María Cid,
Pype Stefan,
Lütjens Robert,
Megens Anton
Publication year - 2015
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.97
Subject(s) - ritanserin , phencyclidine , allosteric modulator , chemistry , pharmacology , agonist , allosteric regulation , antagonist , memantine , nmda receptor , receptor , receptor antagonist , medicine , biochemistry
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 mG lu2 receptor, which also displays 5‐Hydroxytryptamine (5HT 2A ) antagonism after administration in rodents due to a rodent‐specific metabolite. JNJ‐40411813 was compared with the orthosteric mG lu2/3 agonist LY404039 (4‐amino‐2‐thiabicyclo [3.1.0] hexane‐4,6‐dicarboxylic acid 2,2‐dioxide), the selective mG lu2 PAM JNJ‐42153605 (3‐(cyclopropylmethyl)‐7‐(4‐phenylpiperidin‐1‐yl)‐8‐(trifluoromethyl)[1,2,4]triazolo[4,3‐a]pyridine) and the 5HT 2A 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 5HT 2A 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 mG lu2 PAMs and LY404039, but not ritanserin, inhibited conditioned avoidance behavior in rats. Like ritanserin, the mG lu2 ligands antagonized 2,5‐dimethoxy‐4‐methylamphetamine‐induced head twitches in rats. LY404039 but not the mG lu2 PAMs impaired rotarod performance in rats and increased the acoustic startle response in mice. Our results show that although 5HT 2A antagonism has effect in some models, mG lu2 receptor activation is sufficient for activity in several animal models of antipsychotic activity. The mG lu2 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 mG lu2/3 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.