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Funded Studies

Development of L-745,870, a Selective D4 Receptor Antagonist, for the Treatment of Levodopa-induced Dyskinesia

In the 1980s and 90s a novel drug, L-745,870 was developed for the treatment of psychosis in schizophrenia. L-745,870 has excellent characteristics for a drug, and a selective action to block signalling at D4 dopamine receptors. It was found to be safe and well-tolerated in human but was ineffective against psychosis, so its development was terminated. In the last year, we found that L-745,870 reduces the problem of levodopa-induced dyskinesia in pre-clinical models with parkinsonism. We propose to resurrect the development of L-745,870 and move it forward as a treatment for dyskinesia in PD.

Project Description:             
We have generated a development plan for rapid transition to a proof-of-concept clinical trial.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
Levodopa-induced dyskinesia remains one of the major factors limiting the usefulness of current treatments for Parkinson’s disease. The program has potential to provide a pharmacological means to reduce the impact of dyskinesia on the quality of life of people with PD.

Anticipated Outcome:          
If successful the program will define safety and appropriate doses of L-745,870. It will demonstrate the ability of L-745,870 to reduce Levodopa-induced dyskinesia in a small, well-controlled clinical trial in patients with PD. We will thus provide a drug product that can be further assessed for safety and effectiveness in larger trials.

Final Outcome

We demonstrated that L-745,870 can reduce L-DOPA-induced dyskinesia in pre-clinical models. In doing this, we also defined the blood levels of drug that we will need to achieve in clinical trials. The effect of L-745,870 was superior to that of amantadine, the only drug currently available for treating dyskinesia. We manufactured L-745,870 in sufficient quantity, and of sufficient quality, to be employed in clinical trials.  L-745,870 is now ready to be progressed into toxicology studies, and obtain regulatory approval to be moved rapidly into clinical development for dyskinesia in Parkinson’s disease.


  • Tom H. Johnston, PhD

    Toronto Canada

  • Susan H. Fox, MB ChB, MRCP(UK), Ph

    Toronto Canada

  • Daryl Rees, MSc, PhD

    United Kingdom

  • Jonathan M. Brotchie, PhD

    Toronto ON Canada

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