n-(4-(2-methoxyphenoxy)phenyl)-n-(2-2-2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine and Parkinson-Disease

Metabotropic glutamate receptors (mGluRs) have been proposed as novel targets for the treatment of a variety of disorders. Recently, highly selective allosteric modulators of the mGluRs have been developed by several groups. These allosteric compounds provide an unprecedented degree of selectivity for individual mGluRs, allowing for more detailed functional studies on the roles of these receptors. Furthermore, the allosteric approach avoids many of the hurdles associated with the development of direct agonists as drugs, and provides a clear path forward for clinical proof-of-concept studies. Currently, both positive allosteric modulators of mGluR2 and negative allosteric modulators of mGluR5 hold promise as novel anxiolytics, and positive allosteric modulators of mGluR4 appear to be an exciting new target for the treatment of Parkinson's disease.

Topics: Animals; Anxiety; Benzopyrans; Clinical Trials as Topic; Drug Evaluation, Preclinical; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Humans; Imidazoles; Parkinson Disease; Pyridines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Sulfonamides

Psychosis and dyskinesia significantly diminish the quality of life of patients with advanced Parkinson's disease (PD). Available treatment options are unfortunately few and their use is limited by adverse effects. We have recently shown that activation of metabotropic glutamate 2 and 3 (mGlu2/3) receptors produced significant relief of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced psychosis-like behaviours (PLBs) and dyskinesia in experimental models of PD. Here, using the highly-selective mGlu2 positive allosteric modulator (PAM) LY-487,379, we seek to determine the contribution of selective mGlu2 activation on both L-DOPA-induced PLBs and dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. We first determined the pharmacokinetic (PK) profile of LY-487,379 in the common marmoset, following which we administered it (0.1, 1 and 10 mg/kg) or its vehicle to 6 MPTP-lesioned marmosets previously exposed to L-DOPA to elicit stable PLBs and dyskinesia. We found that LY-487,379 provided a ≈45% reduction of the global PLBs observed and reduced global dyskinesia score by ≈ 55%. Moreover, LY-487,379 enhanced the anti-parkinsonian effect of L-DOPA, by reducing global parkinsonian score by ≈ 15%. Our data suggest that selective mGlu2 positive allosteric modulation with LY-487,379 may represent a potential therapeutic approach to alleviate both L-DOPA-induced PLBs and dyskinesia in PD.

Topics: Animals; Antiparkinson Agents; Antipsychotic Agents; Behavior, Animal; Callithrix; Dyskinesia, Drug-Induced; Female; GABA Modulators; Levodopa; Male; MPTP Poisoning; Parkinson Disease; Psychoses, Substance-Induced; Pyridines; Receptors, Metabotropic Glutamate; Sulfonamides