Pramipexole

Pramipexole

Systematic (IUPAC) name
(S)-N6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine
Clinical data
Trade names	Mirapex
AHFS/Drugs.com	monograph
MedlinePlus	a697029
Pregnancy cat.	B3(AU) C(US)
Legal status	℞ Prescription only
Routes	Oral
Pharmacokinetic data
Bioavailability	>90%
Protein binding	15%
Half-life	8-12 hours
Excretion	Urine (90%), Feces (2%)
Identifiers
CAS number	104632-26-0 Y
ATC code	N04BC05
PubChem	CID 119570
DrugBank	APRD00156
ChemSpider	106770 Y
UNII	83619PEU5T Y
KEGG	D05575 Y
ChEBI	CHEBI:8356 Y
ChEMBL	CHEMBL301265 Y
Chemical data
Formula	C10H17N3S
Mol. mass	211.324 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C10H17N3S/c1-2-5-12-7-3-4-8-9(6-7)14-10(11)13-8/h7,12H,2-6H2,1H3,(H2,11,13)/t7-/m0/s1 Y Key:FASDKYOPVNHBLU-ZETCQYMHSA-N Y
N(what is this?)  (verify)

Pramipexole (Mirapex, Mirapexin, Sifrol) is a non-ergoline dopamine agonist indicated for treating early-stage Parkinson's disease (PD) and restless legs syndrome (RLS).^[1] 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.^[2] Pramipexole has shown robust effects on pilot studies in a placebo-controlled proof of concept study in bipolar disorder.^[3] It is also being investigated for the treatment of clinical depression and fibromyalgia.^[4][5][6]

Pharmacology

Pramipexole acts as a partial/full agonist at the following receptors:^[7][8]

• D_2S receptor (K_i = 3.9 nM; IA = 130%)
• D_2L receptor (K_i = 2.2 nM; IA = 70%)
• D₃ receptor (K_i = 0.5 nM; IA = 70%)
• D₄ receptor (K_i = 5.1 nM; IA = 42%)

Pramipexole also possesses low/insignificant affinity (500-10,000 nM) for the 5-HT_1A, 5-HT_1B, 5-HT_1D, and α₂-adrenergic receptors.^[7][9] It has negligible affinity (>10,000 nM) for the D₁, D₅, 5-HT₂, α₁-adrenergic, β-adrenergic, H₁, and mACh receptors.^[7][9] All sites assayed were done using human tissues.^[7][8]

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:^[10][11]

• 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,^[12] even in patients without any prior history of these behaviours.^[13] 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.^[14] 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.^[15]

Chemistry

Pramiprexole can be synthesized from a cyclohexanone derivative by the following route:^[16]

See also

• Dexpramipexole, the enantiomer of pramiproxole
• Piribedil
• Ropinirole
• Rotigotine

References

1. ^ National Prescribing Service (2009). "Pramipexole for Parkinson's Disease". Medicines Update. Available at http://www.nps.org.au/consumers/publications/medicine_update/issues/Pramipexole_for_Parkinsons_disease
2. ^ DeBattista C, Solvason HB, Breen JA, Schatzberg AF. (2000). "Pramipexole augmentation of a selective serotonin reuptake inhibitor in the treatment of depression.". J Clin Psychopharmacol. 20 (2): 274–275. doi:10.1097/00004714-200004000-00029. PMID 10770475. 
3. ^ Biol Psychiatry. 2004 Jul 1;56(1):54-60. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study.Zarate CA Jr, Payne JL, Singh J, Quiroz JA, Luckenbaugh DA, Denicoff KD, Charney DS, Manji HK.PMID: 15219473
4. ^ Lattanzi L, Dell'Osso L, Cassano P, Pini S, Rucci P, Houck PR, Gemignani A, Battistini G, Bassi A, Abelli M, Cassano GB. (2002). "Pramipexole in treatment-resistant depression: a 16-week naturalistic study.". Bipolar Disord. 4 (5): 307–314. doi:10.1034/j.1399-5618.2002.01171.x. PMID 12479663. 
5. ^ Cassano P, Lattanzi L, Soldani F, Navari S, Battistini G, Gemignani A, Cassano GB. (2004). "Pramipexole in treatment-resistant depression: an extended follow-up.". Depress Anxiety. 20 (3): 131–138. doi:10.1002/da.20038. PMID 15549689. 
6. ^ Holman AJ, Myers RR. (2005). "A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications.". Arthritis Rheum. 52 (8): 2495–2505. doi:10.1002/art.21191. PMID 16052595. 
7. ^ ^{a b c d} Kvernmo T, Härtter S, Burger E (August 2006). "A review of the receptor-binding and pharmacokinetic properties of dopamine agonists". Clinical Therapeutics 28 (8): 1065–78. doi:10.1016/j.clinthera.2006.08.004. PMID 16982285. http://linkinghub.elsevier.com/retrieve/pii/S0149-2918(06)00184-6. 
8. ^ ^{a b} Newman-Tancredi A, Cussac D, Audinot V, et al. (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor". The Journal of Pharmacology and Experimental Therapeutics 303 (2): 805–14. doi:10.1124/jpet.102.039875. PMID 12388667. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12388667. 
9. ^ ^{a b} Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes". The Journal of Pharmacology and Experimental Therapeutics 303 (2): 791–804. doi:10.1124/jpet.102.039867. PMID 12388666. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12388666. 
10. ^ "MedlinePlus Drug Information: Pramipexole (Systemic)". United States National Library of Medicine. Archived from the original on 2006-09-26. http://web.archive.org/web/20060926023858/http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203739.html. Retrieved 2006-09-27. 
11. ^ "FDA Prescribing Information: Mirapex (pramipexole dihydrochloride)". Food and Drug Administration (United States). http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020667s014s017s018lbl.pdf. Retrieved 2008-12-31. 
12. ^ Wolters ECh, van der Werf YD, van den Heuvel OA. Parkinson's disease-related disorders in the impulsive-compulsive spectrum. Journal of Neurology. 2008 Sep;255 Suppl 5:48-56. PMID 18787882
13. ^ Bostwick JM, Hecksel KA, Stevens SR, Bower JH, Ahlskog JE. Frequency of new-onset pathologic compulsive gambling or hypersexuality after drug treatment of idiopathic Parkinson disease. Mayo Clinic Proceedings. 2009 Apr;84(4):310-6. doi:10.4065/84.4.310 PMID 19339647
14. ^ USA Today, Not Your Ordinary Side Effects, May 23, 2006
15. ^ Dodd ML, Klos KJ, Bower JH, Geda YE, Josephs KA, Ahlskog JE (September 2005). "Pathological gambling caused by drugs used to treat Parkinson disease". Arch. Neurol. 62 (9): 1377–81. doi:10.1001/archneur.62.9.noc50009. PMID 16009751. 
16. ^ Schneider, Claus S.; Mierau, Joachim (1987). "Dopamine autoreceptor agonists: resolution and pharmacological activity of 2,6-diaminotetrahydrobenzothiazole and an aminothiazole analog of apomorphine". Journal of Medicinal Chemistry 30 (3): 494–8. doi:10.1021/jm00386a009. PMID 3820220. 

External links

• Mirapex.com - Manufacturer's website