Pramipexole

Pramipexole (Mirapex, Mirapexin, Sifrol) is a non-ergoline dopamine agonist indicated for treating early-stage Parkinson's disease (PD) and restless legs syndrome (RLS). It is also sometimes used off-label as a treatment for cluster headache and to counteract the problems with sexual dysfunction experienced by some users of the selective serotonin reuptake inhibitor (SSRI) antidepressants. Pramipexole has shown robust effects on pilot studies in a placebo-controlled proof of concept study in bipolar disorder. It is also being investigated for the treatment of clinical depression and fibromyalgia.

Pharmacology
Pramipexole acts as a partial/full agonist at the following receptors:


 * D2S receptor (Ki = 3.9 nM; IA = 130%)
 * D2L receptor (Ki = 2.2 nM; IA = 70%)
 * D3 receptor (Ki = 0.5 nM; IA = 70%)
 * D4 receptor (Ki = 5.1 nM; IA = 42%)

Pramipexole also possesses low/insignificant affinity (500-10,000 nM) for the 5-HT1A, 5-HT1B, 5-HT1D, and α2-adrenergic receptors. It has negligible affinity (>10,000 nM) for the D1, D5, 5-HT2, α1-adrenergic, β-adrenergic, H1, and mACh receptors. All sites assayed were done using human tissues.

Parkinson's disease is a neurodegenerative disease affecting the substantia nigra, a component of the basal ganglia. The substantia nigra has a high quantity of dopaminergic neurons, which are nerve cells that release the neurotransmitter known as dopamine. When dopamine is released, it may activate dopamine receptors in the striatum, which is another component of the basal ganglia. When neurons of the substantia nigra deteriorate in Parkinson's disease, the striatum no longer properly receives dopamine signals. As a result, the basal ganglia can no longer regulate body movement effectively and motor function becomes impaired. By acting as an agonist for the D2, D3, and D4 dopamine receptors, pramipexole may directly stimulate the underfunctioning dopamine receptors in the striatum, thereby restoring the dopamine signals needed for proper functioning of the basal ganglia.

Side effects
Common side effects of pramipexole may include:


 * Headache
 * Hyperalgesia (body aches and pains)
 * Nausea and vomiting
 * Sedation and somnolence
 * Decreased appetite and subsequent weight loss
 * Orthostatic hypotension (resulting in dizziness, lightheadedness, and possibly fainting, especially when standing up)
 * Insomnia
 * Hallucinations (seeing, hearing, smelling, tasting or feeling things that are not there)
 * Twitching, twisting, or other unusual body movements
 * Unusual tiredness or weakness

Several unusual adverse effects of pramipexole (and related D3-preferring dopamine agonist medications such as ropinirole) may include compulsive gambling, hypersexuality, and overeating, even in patients without any prior history of these behaviours. These behaviors have been reported to manifest in almost 14% of patients on DA agonist therapies. Other compulsive behaviors, such as excessive shopping and compulsive cross-dressing, have been reported. L-DOPA is an indirect acting DA agonist with no specificity for any receptor subtypes. As it is the precursor for dopamine it is rarely associated with these disorders. These side effects are thought to be linked to the D3 activity of pramipexole, as D3 receptors are heavily expressed in brain regions involved in mood, behavior, and reward.

Chemistry
Pramiprexole can be synthesized from a cyclohexanone derivative by the following route: