A novel phosphodiesterase 1 inhibitor reverses L-dopa-induced dyskinesia, but not motivation deficits, in monkeys.

Abstract

The enzyme phosphodiesterase 1 (PDE1) is highly expressed in the striatum and cortex. However, its role in corticostriatal function has not been fully investigated. The present study was aimed at evaluating the therapeutic potential of PDE1 inhibitors in treating motivation deficits and 3,4-dihydroxy-L-phenylalanine (L-dopa)-induced dyskinesia, which are pathological conditions of the corticostriatal system. We used a novel PDE1 inhibitor 3-ethyl-2-{[trans-4-(methoxymethyl)cyclohexyl]oxy}-7-(tetrahydro-2H-pyran-4-yl)-imidazo[5,1-f][1,2,4]triazin-4(3H)-one (DSR-143136), which was identified in our drug discovery program. Motivation in monkeys was measured using a progressive ratio task. L-Dopa-induced dyskinesia and disability scores were measured in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. DSR-143136 had a high selectivity for PDE1 over other PDE families and 67 other biologic targets. A dopamine D1 receptor antagonist SCH-39166 at 0.01, 0.03 and 0.1 mg/kg potently decreased motivation in monkeys. However, DSR-143136 at 0.3 and 3 mg/kg did not affect motivation deficits induced by low-dose SCH-39166 (0.01 mg/kg). On the other hand, DSR-143136 at 3 mg/kg potently decreased L-dopa-induced dyskinesia in the Parkinsonian monkey model. Importantly, this antidyskinesic efficacy was NOT accompanied by detrimental effects on motor function. Further, this compound decreased on-time with marked or severe dyskinesia, without affecting on-time itself. These findings suggest that PDE1 inhibitor could be a therapeutic candidate for treating L-dopa-induced dyskinesia in Parkinson's disease, but not for motivation deficits.

• Authors: Takeshi Enomoto, Tomokazu Nakako, Masao Goda, Erika Wada, Atsushi Kitamura, Yuki Fujii, Kazuhito Ikeda
• Journal: Pharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 205 Pg. 173183 (06 2021) ISSN: 1873-5177 [Electronic] United States
• PMID: 33774006 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Dopamine Antagonists
• Phosphodiesterase Inhibitors
• Levodopa
• Phosphoric Diester Hydrolases

Topics

• Animals
• Behavior, Animal (drug effects)
• Corpus Striatum (drug effects)
• Disease Models, Animal
• Dopamine Antagonists (pharmacology)
• Dyskinesia, Drug-Induced (drug therapy, metabolism)
• Levodopa (adverse effects)
• Macaca mulatta
• Male
• Motivation (drug effects)
• Motor Activity (drug effects)
• Parkinsonian Disorders (drug therapy, metabolism)
• Phosphodiesterase Inhibitors (pharmacology)
• Phosphoric Diester Hydrolases (metabolism)