Unique Antipsychotic Activities of the Selective Metabotropic Glutamate Receptor 1 Allosteric Antagonist 2-Cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one

Abstract

A newly discovered metabotropic glutamate receptor (mGluR) 1 allosteric antagonist, 2-cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one (CFMTI), was tested both in vitro and in vivo for its pharmacological effects. CFMTI demonstrated potent and selective antagonistic activity on mGluR1 in vitro and in vivo after oral administration. CFMTI inhibited L-glutamate-induced intracellular Ca 2ϩ mobilization in Chinese hamster ovary cells expressing human and rat mGluR1a, with IC 50 values of 2.6 and 2.3 nM, respectively. The selectivity of CFMTI to mGluR1 over mGluR5 was Ͼ2000-fold, and CFMTI at 10 M showed no agonistic or antagonistic activities toward other mGluR subtypes and other receptors. It antagonized face-washing behavior in mice induced by (S)-3,5-dihidroxyphenylglycine at a dose range of 3 to 30 mg/kg, for which receptor occupancy was 73 to 94%. As with the classical neuroleptic haloperidol and an atypical antipsychotic, clozapine, orally administered CFMTI reduced methamphetamine-induced hyperlocomotion and disruption of prepulse inhibition (PPI) at the same dose range as required to antagonize the face-washing behavior. CFMTI and clozapine improved ketamine-induced hyperlocomotion, PPI disruption and (5S,10R)-(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801)-induced social withdrawal without any cataleptogenic activities, whereas haloperidol only improved ketamineinduced hyperlocomotion. CFMTI, unlike clozapine, caused neither hypolocomotion nor motor incoordination at therapeutic doses. In c-fos expression studies, CFMTI and clozapine increased the number of fos-positive neurons in the nucleus accumbens and medial prefrontal cortex but not in the dorsolateral striatum. These results suggest that the antipsychotic activities of mGluR1 antagonists are more similar to those of atypical antipsychotics than those of typical antipsychotics.L-Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system (CNS) and acts on both ligand-gated ion channels (ionotropic glutamate receptors; iGluRs) and G protein-coupled metabotropic glutamate receptors (mGluRs). The mGluR family consists of eight recep-A.S. and G.S. contributed equally to this work. Article, publication date, and citation information can be found at

Metabotropic Glutamate Receptors: Potential Drug Targets for Psychiatric Disorders

“…This atypical activity of mGlu1 receptor antagonists is further supported by c-fos induction, in that CFTI induces c-fos in the medial prefrontal cortex and nucleus accumbens, but not in the dorsolateral striatum, which is in line with the results using clozapine [58].…”

“…In contrast, mGlu1 receptor antagonists neither induced catalepsy nor impaired rotarod performance [58,59], suggesting that mGlu1 receptor antagonists may not cause motor dysfunction, unlike the actions of typical antipsychotics. This atypical activity of mGlu1 receptor antagonists is further supported by c-fos induction, in that CFTI induces c-fos in the medial prefrontal cortex and nucleus accumbens, but not in the dorsolateral striatum, which is in line with the results using clozapine [58].…”

“…Antipsychotic-like potentials of mGlu1 receptor antagonists have been further characterized by studies using a potent and selective mGlu1 receptor antagonist CFMTI [58]. As observed with FTIDC, at the doses which antagonizes mGlu1 receptor-mediated behavior (facewashing behavior), CFMTI reduced methamphetamineinduced locomotor hyperactivity and disruption of PPI without affecting spontaneous locomotor activity.…”

“…Of note, these mGlu1 receptor antagonists reduced maximal responses of L-glutamate [57,58], suggesting that both compounds acted as noncompetitive antagonists for the mGlu1 receptor. Thus, FITDC antagonized methamphetamine-induced locomotor hyperactivity and methamphetamine-disrupted PPI [59].…”

Stimulation of Metabotropic Glutamate (mGlu) 2 Receptor and Blockade of mGlu1 Receptor Improve Social Memory Impairment Elicited by MK-801 in Rats

“…For example, mGlu2/3-receptor agonists as well as mGlu2-receptor potentiators have been reported to improve behavioral abnormalities induced by pharmacological and environmental manipulations, which represent both positive and negative symptoms of schizophrenia (5 -7). Likewise, mGlu1-receptor antagonists [4- dihydro-1H-isoindol-1-one (CFMTI) reportedly improved increased locomotor activity and social withdrawal induced by methamphetamine or NMDA-receptor antagonists (8,9). Therefore, both the stimulation of the mGlu2/3 receptor and the blockade of the mGlu1 receptor may be useful approaches to treating the positive and negative symptoms of schizophrenia.…”