Movement disorders are conditions of the nervous system that affect the intentional ability to produce and control body movement, its speed, fluency, quality, and ease. They usually manifest as abnormal, involuntary movements (dyskinesia) or postures (akinesia) such as chorea (involuntary, rapid, irregular, jerky movements), ballismus (involuntary movements similar to chorea but more violent, explosive), dystonia (involuntary sustained muscle spasms, usually producing twisting, repetitive movements or abnormal postures and positions), myoclonus (twitching or intermittent muscular spasms producing rapid, brief, movements), athetosis (repetitive involuntary, slow, sinuous, writhing movements, especially severe in the hands), akathisia (inability to sit still or remain motionless), ataxia (lack of coordination, often producing jerky movements), syncinesia (the occurrence simultaneously of both voluntary and involuntary movements), tics (involuntary muscle contractions that interrupt normal activities), bradykinesia (slowness or poverty of movement) or tremor (involuntary rhythmic muscle contraction and relaxation involving to and from movements).
Such disorders can occur as a consequence of inherited or acquired diseases, and/or they can result from medical treatments. They are often associated with basal ganglia dysfunction and impaired regulation of dopamine neurotransmission.
For example, Parkinson's disease is caused by degeneration of nerve cells in the substantia nigra and is characterized by pronounced movement impairment, including bradykinesia, rigidity and/or tremor. The quality of life of the patient is progressively decreased, particularly because of disturbed gait and balance. Falls and injuries are a common consequence of balance problems, and represent a threat to the health status and independence of the Parkinson's patient. The symptomatic therapy of Parkinson's disease mainly consists in administering to the patient dopamine-replacing agents that alleviates motor symptoms and greatly improve the quality of life of patients. Levodopa (3,4-hydroxyphenylalanine) which remains the gold standard for treatment of Parkinson's disease, acts as a dopamine prodrug, which is bio-metabolized into dopamine in the brain. Dopamine, in turn, activates dopamine receptors. Direct-acting dopamine receptor agonists such as bromocriptine, lisuride, pramipexole, ropinirole and pergolide are also used mainly in the earlier stages of Parkinson's disease, but are less efficacious than levodopa in moderate to severe Parkinson's disease. However, following long-term dopamine agonist or Levodopa dopamine-replacement therapies, these agents become less efficacious, with the patients switching alternatively from responding periods to non responding periods, and the appearance of side effects such as other involuntary movements, called dyskinesia induced by dopamine-replacement therapy. Parkinson's disease patients may cycle between “on” periods which are complicated by dyskinesia, and “off” periods in which they are severely parkinsonian, and experience profound disability despite the fact that the dopamine replacement remains an effective anti-Parkinson therapy, albeit at narrower and narrower doses, throughout the course of the disease.
Another example of pathology associated with movement disorders is Huntington's disease, a rare, inherited disease that causes chronic progressive chorea and problems with movement coordination. In the early stage of Huntington's disease, slowing of movements, chorea, and occasional loss of balance are significant symptoms. As the disease progresses, balance and walking problems become more serious and incapacitating.
Other examples can be cited such as Tourette's syndrome (an inherited disorder characterized by multiple motor and vocal tics), dystonia (a disorder associated with slowness of movement, poor balance and difficulty moving around) and tardive dyskinesia (a disorder that can result from the use of a number of different pharmacological agents, such as antipsychotic drugs that target the dopamine system, and associated with facial tics and movements of the jaw, lips and tongue).
Many approaches of treatments for movement disorders have been investigated over the past years, few approved therapies having either poor efficacy or tolerability issues. In particular, agonists of the serotonin 5-hydroxytryptamine (5-HT) 1A receptor have been shown to ameliorate and/or prevent some aspects of movement disorders, such as extrapyramidal side effects associated with neuroleptics treatment, dyskinesia that arise from long-term Levodopa therapy in Parkinson's disease (Shimizu et al. 2013 Aging and disease 4(1):1-13) or involuntary movement in Huntington's disease (Roppongi et al 2007 Prog Neuropsychopharmacol Biol Psychiatry 31(1):308-310).
Befiradol, [(3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]methanone], is a selective and high efficacy serotonin 5-HT1A receptor agonist (Colpaert et al. 2002 Neuropharmacology 43: 945-958), discovered by Pierre Fabre Laboratories (U.S. Pat. Nos. 6,020,345; 7,208,603). The structural formula of befiradol is shown below:

Befiradol is intended to be of benefit for the treatment of Levodopa-induced dyskinesia and other movement disorders. However, its use to treat patients suffering from movements disorders could be very limited because of its potential side-effects including dizziness and nausea. Indeed, these types of side effects are the most incapacitating in these patient populations because they already experience problems with balance, nausea and emesis, resulting from the movement disorder itself, the underlying pathology and/or the treatment they undergo, such as Levodopa or dopamine agonist administration.
Thus, there is a great need of finding a method to use befiradol to treat movement disorders that would minimize side effects such as dizziness and nausea.