Dopamine D-1 receptor agonists - The way forward for the treatment of Parkinson's disease?

The pharmacotherapy of Parkinson's disease mainly consists of treatment wit h levodopa and/or dopamine receptor agonists, which compensate for the loss of dopamine in the CNS that characterises the disease. Although treatment with levodopa is more effective than that with dopamine receptor agonists, the former frequently causes serious adverse effects, e.g. wearing-off phen omena and dyskinesias. Levodopa (after conversion to dopamine) stimulates d opamine D-1 and D-2 receptors, whereas the presently available dopamine ago nists act mainly on D-2 receptors. Therefore, the D-1 receptor might be a p otential target for pharmacotherapy in Parkinson's disease. However, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesione d monkey model of Parkinson's disease, the partial D-1 agonist SKF-38393 fa iled to stimulate motor behaviour. Newly developed agents that are full ago nists at the D-1 receptor do stimulate motor behaviour of MPTP-lesioned mon keys and act synergistically with D-2 receptor agonists. Nonetheless, sever al of these compounds lose their efficacy in stimulating motor behaviour up on sustained administration and induce dyskinetic behaviour. Moreover, thes e compounds are likely to have the potential to induce epileptic seizures. Therefore, the potential Value of the newly developed D-1 receptor agonists in the treatment of Parkinson's disease seems limited.