n-(4-(2-methoxyphenoxy)phenyl)-n-(2-2-2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine and Dyskinesia--Drug-Induced

Antagonising serotonin (5-HT) type 2A receptors (5-HT. Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and psychosis-like behaviours (PLBs) were administered L-3,4-dihydroxyphenylalanine (L-DOPA) in combination with vehicle or the 5-HT. EMD-281,014 reduced dyskinesia and PLBs by up to 47% and 40%, respectively (both P < 0.001). The addition of LY-354,740, LY-487,379 and LY-354,740/LY-487,379 decreased dyskinesia by 56%, 65% and 77%, while PLBs were diminished by 55%, 63% and 71% (all P < 0.001). All treatment combinations provided anti-dyskinetic and anti-psychotic benefits significantly greater than those conferred by EMD-281,014 alone (all P < 0.05). The combination of EMD-281,014/LY-354,740/LY-487,379 resulted in anti-dyskinetic and anti-psychotic effects significantly greater than those conferred by EMD-281,014 with either LY-354,740 or LY-487,379 (both P < 0.05). No deleterious effects on L-DOPA anti-parkinsonian action were observed.. Our results suggest that combining 5-HT

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Behavior, Animal; Bridged Bicyclo Compounds; Callithrix; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Indoles; Levodopa; Male; Parkinsonian Disorders; Piperazines; Psychotic Disorders; Pyridines; Receptors, Metabotropic Glutamate; Serotonin 5-HT2 Receptor Antagonists; 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