D-512, a novel dopamine D2/3 receptor agonist, demonstrates greater anti-Parkinsonian efficacy than ropinirole in Parkinsonian rats

Br J Pharmacol. 2017 Sep;174(18):3058-3071. doi: 10.1111/bph.13937. Epub 2017 Aug 11.


Background and purpose: Symptoms of Parkinson's disease are commonly managed using selective dopamine D2/3 receptor agonists, including ropinirole. While D2/3 agonists are useful in early-stage Parkinson's disease, they tend to lose efficacy in later disease stages and do not appear to modify disease progression. We have recently developed a novel 'multifunctional' compound, D-512: a high-affinity D2/3 receptor agonist with antioxidant and other neuroprotective properties that may limit Parkinson's disease progression. This study sought to compare the anti-Parkinsonian properties of the clinically used compound, ropinirole, with those of the novel compound, D-512.

Experimental approach: A rat model of Parkinson's disease was created by unilaterally infusing 6-hydroxydopamine, a dopamine neurotoxin, into the medial forebrain bundle. D-512 was compared with ropinirole for ability to stimulate spontaneous motor activity and reverse Parkinsonian akinesia. These beneficial effects were compared against each drug's liability to provoke dyskinesia, a common motor side effect.

Key results: Both compounds increased spontaneous movement, but D-512 showed a longer duration of action. Only D-512 was able to significantly reverse forelimb akinesia. Drug-induced dyskinesia was similar for equivalent doses.

Conclusions and implications: Compared with ropinirole, D-512 showed greater peak-dose efficacy and a longer duration of action, despite a similar side-effect profile. Our results add to earlier data showing that D-512 is superior to available D2/3 agonists and could merit clinical investigation.

MeSH terms

  • Animals
  • Antiparkinson Agents / chemistry
  • Antiparkinson Agents / pharmacology*
  • Disease Models, Animal
  • Dopamine Agonists / chemistry
  • Dopamine Agonists / pharmacology*
  • Dose-Response Relationship, Drug
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Male
  • Molecular Structure
  • Parkinson Disease / drug therapy*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / agonists*
  • Receptors, Dopamine D3 / agonists*
  • Structure-Activity Relationship
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*


  • Antiparkinson Agents
  • D-512 compound
  • Dopamine Agonists
  • Indoles
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Thiazoles
  • ropinirole