From the cell to the clinic: A comparative review of the partial D2/D3 receptor agonist and α2-adrenoceptor antagonist, piribedil, in the treatment of Parkinson's disease

Though l-3,4-dihydroxyphenylalanine (L-DOPA) is universally employed for alleviation of motor dysfunction in Parkinson's disease (PD), it is poorly-effective against co-morbid symptoms like cognitive impairment and depression. Further, it elicits dyskinesia, its pharmacokinetics are highly variable, and efficacy wanes upon long-term administration. Accordingly, “dopaminergic agonists” are increasingly employed both as adjuncts to L-DOPA and as monotherapy. While all recognize dopamine D2 receptors, they display contrasting patterns of interaction with other classes of monoaminergic receptor. For example, pramipexole and ropinirole are high efficacy agonists at D2 and D3 receptors, while pergolide recognizes D1, D2 and D3 receptors and a broad suite of serotonergic receptors. Interestingly, several antiparkinson drugs display modest efficacy at D2 receptors. Of these, piribedil displays the unique cellular signature of: 1), signal-specific partial agonist actions at dopamine D2and D3 receptors; 2), antagonist properties at α2-adrenoceptors and 3), minimal interaction with serotonergic receptors. Dopamine-deprived striatal D2 receptors are supersensitive in PD, so partial agonism is sufficient for relief of motor dysfunction while limiting undesirable effects due to “over-dosage” of “normosensitive” D2 receptors elsewhere. Further, α2-adrenoceptor antagonism reinforces adrenergic, dopaminergic and cholinergic transmission to favourably influence motor function, cognition, mood and the integrity of dopaminergic neurones. In reviewing the above issues, the present paper focuses on the distinctive cellular, preclinical and therapeutic profile of piribedil, comparisons to pramipexole, ropinirole and pergolide, and the core triad of symptoms that characterises PD-motor dysfunction, depressed mood and cognitive impairment. The article concludes by highlighting perspectives for clarifying the mechanisms of action of piribedil and other antiparkinson agents, and for optimizing their clinical exploitation.