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Receptor-Binding and Pharmacokinetic Properties of Dopaminergic Agonists

Receptor-Binding and Pharmacokinetic Properties of Dopaminergic Agonists

  1. Anonymous
    Current Topics in Medicinal Chemistry, 2008, 8, 1049-1067
    Trond Kvernmo, John Houben and Ingebrigt Sylte

    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 D1 subreceptor and increase dyskinesia. Furthermore, valvular heart disease (VHD) and pulmonary and retroperitoneal fibrosis appear to represent a class effect of 8��-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 D2 agonism. However, in monotheraphy, the selective D2-receptor DA agonist sumanirole seemed less effective than ropinirole which
    is selective for D2- like DA-receptors (D2, D3 and D4). Given as adjunctive to L-dopa both drugs had equal efficacy on motor-symptoms, indicating that D2-receptor activity must be accompanied with stimulation of other DA receptors for optimizing the efficacy on motor symptoms. Striatal D3 receptor loss may be more important than D2 receptor loss for
    reduced response to dopaminergic treatment. D3 stimulation may also be beneficial for the non-motor symptom depression/mood in PD and for neuron-protection. This makes D3-receptors a potential therapeutic target in PD. 5-HT1Areceptor
    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 D3 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.