A novel phosphodiesterase 1 inhibitor reverses L-dopa-induced dyskinesia, but not motivation deficits, in monkeys
| Autor: | Masao Goda, Kazuhito Ikeda, Atsushi Kitamura, Erika Wada, Takeshi Enomoto, Tomokazu Nakako, Yuki Fujii |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Dyskinesia Drug-Induced Phosphodiesterase Inhibitors Clinical Biochemistry Striatum Motor Activity PDE1 Pharmacology Toxicology Biochemistry Levodopa 03 medical and health sciences Behavioral Neuroscience chemistry.chemical_compound 0302 clinical medicine Dopamine receptor D1 Parkinsonian Disorders Dopamine medicine Animals Biological Psychiatry Motivation Behavior Animal Phosphoric Diester Hydrolases business.industry MPTP Antagonist Phosphodiesterase Macaca mulatta Corpus Striatum 030227 psychiatry Disease Models Animal chemistry Dyskinesia Dopamine Antagonists medicine.symptom business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Pharmacology Biochemistry and Behavior. 205:173183 |
| ISSN: | 0091-3057 |
| DOI: | 10.1016/j.pbb.2021.173183 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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