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.

酶磷酸二酯酶 1 (PDE1) 在纹状体和皮质中高度表达。然而，其在皮质纹状体功能中的作用尚未得到充分研究。本研究旨在评估 PDE1 抑制剂在治疗动机缺陷和 3,4-二羟基-L-苯丙氨酸（左旋多巴）引起的运动障碍，这是皮质纹状体系统的病理状况。我们使用了一种新型 PDE1 抑制剂 3-ethyl-2-{[trans-4-(甲氧基甲基)cyclohexyl]oxy}-7-(tetrahydro-2H-pyran-4-yl)-imidazo[5,1-f][1 ,2,4]triazin-4(3H)-one (DSR-143136)，这是在我们的药物发现计划中发现的。使用渐进比率任务测量猴子的动机。在 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 治疗的猴子中测量了左旋多巴引起的运动障碍和残疾评分。DSR-143136 对 PDE1 的选择性高于其他 PDE 家族和 67 个其他生物靶标。多巴胺 D ₁0.01、0.03 和 0.1 mg/kg 的受体拮抗剂 SCH-39166 可有效降低猴子的动力。然而，0.3 和 3 mg/kg 的 DSR-143136 不影响低剂量 SCH-39166 (0.01 mg/kg) 引起的动机缺陷。另一方面，3 mg/kg 的 DSR-143136 有效降低了帕金森病猴模型中左旋多巴诱导的运动障碍。重要的是，这种抗运动障碍功效并未伴随对运动功能的不利影响。此外，这种化合物会降低准时并伴有明显或严重的运动障碍，而不会影响准时本身。这些发现表明 PDE1 抑制剂可能是治疗帕金森病中左旋多巴诱导的运动障碍的治疗候选药物，但不能用于治疗动机缺陷。