Dopamine D3 agonists in the treatment of Parkinson's disease.

Parkinson's disease (PD) is t he second most common form of neurodegenerative disorders that results from the progressive loss of dopaminergic neurons in the midbrain substantia nigra pars compacta (SNpc) triggering profound motor perturbation, as well as cognitive, sensory and mood deficits. Although these symptoms can be improved using currently available dopamine replacement strategies, they are not able to slow the neurodegenerative process that underlies PD progression. Following the discovery of the D3 receptor from molecular cloning, it has gained much attention as a potential therapeutic target for the treatment of PD due to their localization in the limbic regions of the brain as well as pharmacologic similarity to the D2 receptor subtype. Of particular interest, D3 receptor-selective agonists appear to have neuroprotective effects apart from their ability to relieve PD symptoms. Owing to the distinct significance of D3 receptor in mediating diverse neurological effects, it represents a unique target for therapeutic intervention in PD with much less undesirable side effects. Herein, we review progress in the development of D3 receptor-selective agonist molecules having a broad spectrum of affinities, selectivities as well as unique pharmacological properties directed at slowing the neurodegeneration process.