Pharmacological Characterization of a New, Orally Active and Potent Allosteric Metabotropic Glutamate Receptor 1 Antagonist, 4-[1-(2-Fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC)

Abstract

A highly potent and selective metabotropic glutamate receptor (mGluR) 1 antagonist, 4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2, 3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC), is described. FTIDC inhibits, with equal potency, L-glutamate-induced intracellular Ca 2ϩ mobilization in Chinese hamster ovary cells expressing human, rat, or mouse mGluR1a. The IC 50 value of FTIDC is 5.8 nM for human mGluR1a and 6200 nM for human mGluR5. The maximal response in agonist concentration-response curves was reduced in the presence of higher concentrations of FTIDC, suggesting the inhibition in a noncompetitive manner. FTIDC at 10 M showed no agonistic, antagonistic, or positive allosteric modulatory activity toward mGluR2, mGluR4, mGluR6, mGluR7, or mGluR8. FTIDC did not displace [ 3 H]L-quisqualate binding to human mGluR1a, indicating FTIDC is an allosteric antagonist. Studies using chimeric and mutant receptors of mGluR1 showed that transmembrane (TM) domains 4 to 7, especially Phe801 in TM6 and Thr815 in TM7, play pivotal roles in the antagonism of FTIDC. FTIDC inhibited the constitutive activity of mGluR1a, suggesting that FTIDC acts as an inverse agonist of mGluR1a. Intraperitoneally administered FTIDC inhibited face-washing behavior elicited by a group I mGluR agonist, (S)-3,5-dihydroxyphenylglycine in mice at doses that did not produce motor impairment. Oral administration of FTIDC also inhibited the face-washing behavior. FTIDC is a highly potent and selective allosteric mGluR1 antagonist and a compound having oral activity without species differences in its antagonistic activity on recombinant human, mouse, and rat mGluR1. FTIDC could therefore be a valuable tool for elucidating the functions of mGluR1 not only in rodents but also in humans.Metabotropic glutamate receptors (mGluRs) are G proteincoupled receptors, and they are thought to contribute to the fine-tuning of fast synaptic response, neuronal excitability, and neurotransmitter release. To date, eight mGluR subArticle, publication date, and citation information can be found at

Metabotropic Glutamate Receptors: Potential Drug Targets for Psychiatric Disorders

“…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].…”

Correlation of Receptor Occupancy of Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Mouse Brain With In Vivo Activity of Allosteric mGluR1 Antagonists

“…Systemic administration of FTIDC inhibits the behavioral change. These findings indicate that FTIDC is a novel and excellent allosteric mGluR1 antagonist with respect to antagonist potency, selectivity, species difference, and brain penetrability (24). Therefore, radiolabelled FTIDC could be useful for elucidating the function of mGluR1.…”

“…2+ mobilization Functional assays based on intracellular Ca 2+ mobilization were conducted according to previously described methods (24). In brief, CHO-hmGluR1a was seeded at 5 × 10 4 cells /well in a 96-well plate and cultured overnight.…”

“…4-[1-(2-Fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC) is a recently identified allosteric mGluR1 antagonist with a novel chemical structure (24). The compound has high selectivity and equal inhibitory activity toward recombinant human, rat, and mouse mGluR1.…”

Metabotropic Receptors for Glutamate and GABA

“…CPCCOEt was later discovered to bind to an allosteric domain and this highlighted the capacity of ligands to bind in allosteric binding modes, thereby modulating orthosteric ligand function (Litschig et al, 1999). Thereafter, structurally distinct NAMs for mGlu 1 were also discovered such as BAY36-7620 and FTIDC (Carroll et al, 2001;Suzuki et al, 2007). mGlu 5 selective NAMs were also identified of which the two flagship molecules were MPEP and MTEP, both providing good potency and selectivity (Anderson et al, 2002;.…”