The elegance of dopamine receptor selectivity in Parkinson's disease

Dopamine receptor pathophysiology in Parkinson's disease

Parkinson's disease is a chronic neurodegenerative disorder that is characterized by progressive and debilitating motor symptoms, which are the hallmarks of the disease and a major focus of current therapeutic intervention.^1-4 Although Parkinson's disease is typically diagnosed when motor symptoms are present, the disease process usually begins before these symptoms occur.⁴ People living with Parkinson's disease also experience nonmotor symptoms.⁵

In Parkinson's disease, dopamine is the most disrupted neurotransmitter and acts through multiple pathways in the human brain.^6,7 Let's look more into a few of these pathways in healthy conditions. One major pathway is the nigrostriatal pathway, which is involved with motor control.⁷ Other key pathways are the mesolimbic and mesocortical pathways, in which different areas containing dopamine neurons play a role in reward and cognition, respectively.^7,8 Within the pathways there are 5 different receptor subtypes through which dopamine signaling can occur.⁹ D2, D3, and D4 dopamine receptors are referred to as D2-like receptors.^2,10-12 These receptor subtypes are the primary targets of currently approved dopamine agonists.² The other two dopamine receptors, D1 and D5, are referred to as D1-like receptors.^2,10-12 Within the nigrostriatal pathway in Parkinson's disease dopamine-producing neurons degenerate in the substantia nigra, leading to a loss of dopamine signaling and the emergence of motor symptoms.^3,13-14 Treatment focuses on offsetting the effects of these degenerating neurons by restoring dopamine signaling to improve some of the motor symptoms.^2,3,7 Now let's review some of the current treatment options.

Levodopa, which is a dopamine precursor that gets converted into dopamine, is the current oral standard-of-care for Parkinson's disease.^10,15 It leads to the activation of all dopamine receptors along the dopamine pathways.^2,10,15 Over time, neuronal degeneration, neuronal death, and pulsatile stimulation of receptors can lead to unpredictable symptom control with increased dyskinesia.^6,15-18 Other currently approved therapies include dopamine agonists, which target the D2 receptor subfamily, primarily at the D2 and D3 receptors.^2,15 However, D2/D3 agonists activate receptors that are located throughout many parts of the brain including areas outside of the nigrostriatal pathway that may not be degenerated.^2,15 This wide activation of D2/D3 receptors is primarily associated with potential burdensome nonmotor side effects, such as hallucinations, impulse control disorders, orthostatic hypotension, and excessive daytime sleepiness.^2,15 These symptoms may contribute to the emotional and physical burden of Parkinson's disease.¹⁹ Given that current treatment options may activate off-target dopamine receptors along a wide array of dopamine pathways, a more selective approach could be evaluated.^2,10,12,15 For instance, selectively targeting D1/D5 receptors through agonists is a potential approach in the treatment of Parkinson's disease.^20,21 A targeted approach to dopamine signaling may be achieved by selective D1/D5 dopamine receptor agonism.^20,21 This selective D1/D5 agonism may avoid D2/D3/D4 receptor agonism.^20,21 Selective targeting of D1-like receptors may provide a potential new approach to the treatment of Parkinson's disease.^20,21

References:

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2. Isaacson SH, Hauser RA, Pahwa R, Gray D, Duvvuri S. Dopamine agonists in Parkinson's disease: Impact of D1-like or D2-like dopamine receptor subtype selectivity and avenues for future treatment. Clin Park Relat Disord. 2023;9:100212. doi:10.1016/j.prdoa.2023.100212
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16. Erekat NS. Apoptosis and its role in Parkinson's disease. In: Parkinson's Disease: Pathogenesis and Clinical Aspects. Stoker TB, Greenland JC, eds. Codon Publications; 2018. Accessed February 21, 2025. http://www.ncbi.nlm.nih.gov/books/NBK536726/
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20. Riesenberg R, Werth J, Zhang Y, Duvvuri S, Gray D. PF-06649751 efficacy and safety in early Parkinson’s disease: a randomized, placebo-controlled trial. Ther Adv Neurol Disord. 2020;13:1756286420911296. doi:10.1177/1756286420911296 
21. Sohur US, Gray DL, Duvvuri S, Zhang Y, Thayer K, Feng G. Phase 1 Parkinson’s disease studies show the dopamine D1/D5 agonist PF-06649751 is safe and well tolerated. Neurol Ther. 2018;7(2):307-319. doi:10.1007/s40120-018-0114-z