Parkinson's Disease — SLV30B
Parkinson's Disease is a result of a deficiency in the amount of dopamine in the brain, caused by the degeneration of the substantia nigra. Its main symptoms include tremor, rigidity and bradykinesia, with many sufferers also experiencing such secondary effects as depression, dementia and problems with sleeping.
Standard treatments rely on supplementing the amount of dopamine by administering levodopa, a prodrug that is converted to dopamine within the brain. Alternatively, anticholinergic drugs can be used to restore, to a degree, the balance between dopamine and acetylcholine in the brain. However, treatments like have no effect on the progression of the disease.
More recent attempts to find a dopamine D2 agonist to use instead of L-dopa led to the discovery of the two alkaloids bromocryptine and pergolide, and the non-ergot compounds ropinirole and pramipexole. Solvay Pharmaceuticals has been looking at a partial D2 agonist, in the hope that such a drug would have a more long-lasting effect with fewer side-effects. Using a partial agonist may well reduce the propensity of the D2 receptors to become desensitised.
The programme led to the development of SLV3081, which was found to be a very potent partial dopamine D2 receptor agonist, which is also a weak full 5-HT1A agonist. This means that not only does it have antiparkinsonism activity, but it also acts as an antidepressant and anxiolytic.2
Its safety and tolerability have been studied in 51 healthy male subjects. Twenty-seven of these received one or more single doses of 0.01–0.5mg, and the remainder multiple doses, gradually titrated upwards, to a maximum of 1mg. The single-dose study showed side-effects at doses of 0.2mg and higher. However, the multiple dose studies showed the compound to be well-tolerated in doses of up to 1mg, indicating that slow upward titration of doses makes for much better tolerance.
The drug is rapidly absorbed, with peak concentrations being achieved within 30min to 4hr after the dose. Excretion of unmetabolised drug in the urine was found to be low. The clinical data collected thus far indicate that SLV308 may be a useful therapeutic agent for the treatment of Parkinson's disease.