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[摘要]：This review describes symptoms and pathophysiology of Parkinson's diseases (PD) and restless legs syndrome (RLS), and discusses the relationship between clinical outcome of DA agonists and their receptor-binding and pharmacokinetics. Oral DA agonists are divided into 2 classes; the ergots and the non-ergots. Both classes are in general equally effective against PD motor symptoms. Ergots (apart from bromocriptine) stimulate the DA D-1 subreceptor and increase dyskinesia. Furthermore, valvular heart disease (VHD) and pulmonary and retroperitoneal fibrosis appear to represent a class effect of 8 beta-aminoergolines as cabergoline and pergolide The side effects profile therefore seems more beneficial for non-ergots than ergots. The main improvement of motor functions by DA agonists is related to D-2 agonism. However, in monotheraphy, the selective D-2-receptor DA agonist sumanirole seemed less effective than ropinirole which is selective for D-2-like DA-receptors (D-2, D-3 and D-4). Given as adjunctive to L-dopa both drugs had equal efficacy on motor-symptoms, indicating that D-2-receptor activity must be accompanied with stimulation of other DA receptors for optimizing the efficacy on motor symptoms. Striatal D-3 receptor loss may be more important than D-2 receptor loss for reduced response to dopaminergic treatment. D-3 stimulation may also be beneficial for the non-motor symptom depression/mood in PD and for neuron-protection. This makes D-3-receptors a potential therapeutic target in PD. 5-HT1A-receptor agonism and 2 adrenergic antagonism may contribute to prevention of dyskinesia. However, 5-HT-receptor activity is also associated with side effects. 5-HT2B agonism (and possibly 5-HT1B agonism) is associated with fibrotic reactions, and valvular heart disease (VHD). By interfering with the CYP450 system DA agonists may contribute to drug-drug interactions. Lack of CYP2D6 activity is also suggested as important for etiology and CNS-symptoms of PD. Based on current knowledge D2-like receptor activities (preferences for the D-3 receptor) seem most beneficial. 5-HT1A-receptor agonism (prevention of dyskinesia), 5-HT2B antagonism or no 5-HT2B-receptor activity also seems beneficial. Development of DA agonists containing these properties, without interfering with CYP2D6 may be beneficial. |
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