Pramipexole

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Pramipexole
Pramipexole.svg
Pramipexole ball-and-stick.png
Systematic (IUPAC) name
(S)-N  6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine
Clinical data
Trade names Mirapex, Mirapexin, Sifrol
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 YesY
ATC code N04BC05
PubChem CID 119570
IUPHAR ligand 953
DrugBank DB00413
ChemSpider 106770 YesY
UNII 83619PEU5T YesY
KEGG D05575 YesY
ChEBI CHEBI:8356 YesY
ChEMBL CHEMBL301265 YesY
Chemical data
Formula C10H17N3S 
Mol. mass 211.324 g/mol
 YesY (what is this?)  (verify)

Pramipexole (Mirapex, Mirapexin, Sifrol) is a dopamine agonist of the non-ergoline class indicated for treating Parkinson's disease (PD)[1] and restless legs syndrome (RLS).[2]

Pharmacology[edit]

Pramipexole acts as a partial/full agonist at the following receptors:[3][4]

Pramipexole also possesses low/insignificant affinity (500–10,000 nM) for the 5-HT1A, 5-HT1B, 5-HT1D, and α2-adrenergic receptors.[3][5] It has negligible affinity (>10,000 nM) for the D1, D5, 5-HT2, α1-adrenergic, β-adrenergic, H1, and mACh receptors.[3][5] All sites assayed were done using human tissues.[3][4]

While pramipexole is used clinically (see below), its D3-preferring receptor binding profile has made it a popular tool compound for preclinical research. For example, pramipexole has been used (in combination with D2- and or D3-preferring antagonists) to interrogate the role of D3 receptor function in rodent models and tasks for neuropsychiatric disorders.[6] Of note, it appears that pramipexole, in addition to having effects on dopamine D3 receptors, may also affect mitochondrial function via a mechanism that remains less understood. A pharmacological approach to separate dopaminergic from non-dopaminergic (e.g. mitochondrial) effects of pramipexole has been to study the effects of the R-stereoisomer of pramipexole (which has much lower affinity to the dopamine receptors when compared to the S-isomer) side-by-side with the effects of the S-isomer.[7]

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.

Bipolar depression[edit]

In a single controlled study of twenty one patients, pramipexole was found to be highly effective in the treatment of bipolar depression. Treatment was initiated at 0.125 mg three times a day and increased at a rate of 0.125 mg three times a day to a limit of 4.5 mg daily until the patients' condition satisfactorily responded to the medication or they could not abide the side effects. The final average dosage was 1.7 ± 0.9 mg daily. The incidence of hypomania in the treatment group was no greater than in the control group.[8]

Unipolar depression[edit]

In one controlled study, pramipexole was shown to be efficacious in the treatment of unipolar depression.[9]cited in[8]

Side effects[edit]

Common side effects of pramipexole may include:[10][11]

Several unusual adverse effects of pramipexole (and related D3-preferring dopamine agonist medications such as ropinirole) may include compulsive gambling, punding, hypersexuality, and overeating,[12] even in patients without any prior history of these behaviours.[13]

Chemistry[edit]

Pramiprexole can be synthesized from a cyclohexanone derivative by the following route:[14] Pramipexole.png

Research[edit]

Pramipexole has been evaluated for the treatment of cluster headache and to counteract problems with sexual dysfunction experienced by some users of selective serotonin reuptake inhibitor (SSRI) antidepressants.[15] Pramipexole has shown effects on pilot studies in a placebo-controlled proof of concept study in bipolar disorder.[8][16][17] It is also being investigated for the treatment of clinical depression and fibromyalgia.[18][19][20]

See also[edit]

References[edit]

  1. ^ "Once-daily MIRAPEX ER now approved by FDA for both early and advanced Parkinson’s disease". Boehringer Ingelheim Pharmaceuticals, Inc. Retrieved 19 December 2013. 
  2. ^ 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
  3. ^ 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. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ Weber, M; Chang W; Breier M; Ko D; Swerdlow NR (December 2008). "Heritable strain differences in sensitivity to the startle gating-disruptive effects of D2 but not D3 receptor stimulation". Behav Pharmacol 19 (8): 786–795. doi:10.1097/FBP.0b013e32831c3b2b. PMC 3255557. PMID 19020413. 
  7. ^ Chang, W; Weber M; Breier MR; Saint Marie RL; Hines SR; Swerdlow NR (February 2012). "Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats". Brain Res 1437: 69–76. doi:10.1016/j.brainres.2011.12.007. PMID 22227455. 
  8. ^ a b c Zarate CA, Payne JL, Singh J, et al. (July 2004). "Pramipexole for bipolar II depression: a placebo-controlled proof of concept study". Biol. Psychiatry 56 (1): 54–60. doi:10.1016/j.biopsych.2004.03.013. PMID 15219473. 
  9. ^ Corrigan MH, Denahan AQ, Wright CE, Ragual RJ, Evans DL (2000): Comparison of pramipexole, fluoxetine, and placebo in patients with major depression. Depress Anxiety 11:58 –65.
  10. ^ "MedlinePlus Drug Information: Pramipexole (Systemic)". United States National Library of Medicine. Archived from the original on 2006-09-26. Retrieved 2006-09-27. 
  11. ^ "FDA Prescribing Information: Mirapex (pramipexole dihydrochloride)". Food and Drug Administration (United States). Retrieved 2008-12-31. 
  12. ^ Wolters ECh, van der Werf YD, van den Heuvel OA (September 2008). "Parkinson's disease-related disorders in the impulsive-compulsive spectrum". J. Neurol. 255 Suppl 5: 48–56. doi:10.1007/s00415-008-5010-5. PMID 18787882. 
  13. ^ Bostwick JM, Hecksel KA, Stevens SR, Bower JH, Ahlskog JE (April 2009). "Frequency of new-onset pathologic compulsive gambling or hypersexuality after drug treatment of idiopathic Parkinson disease". Mayo Clin. Proc. 84 (4): 310–6. doi:10.4065/84.4.310. PMC 2665974. PMID 19339647. 
  14. ^ 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. 
  15. ^ 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. 
  16. ^ Goldberg JF, Burdick KE, Endick CJ (March 2004). "Preliminary, randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment resistant bipolar depression.". American Journal of Psychiatry 161 (3): 161:564–566. doi:10.1176/appi.ajp.161.3.564. PMID 14992985. 
  17. ^ Guy M. Goodwina, A. Martinez-Aranb, David C. Glahn c, Eduard Vieta b (November 2008). "Cognitive impairment in bipolar disorder: Neurodevelopment or neurodegeneration? An ECNP expert meeting report". European Neuropsychopharmacology 18 (11): 787–793. doi:10.1016/j.euroneuro.2008.07.005. PMID 18725178. 
  18. ^ 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. 
  19. ^ Cassano P, Lattanzi L, Soldani F, Navari S, Battistini G, Gemignani A, Cassano GB. (2004). "Pramipexole in treatment-resistant depression: an extended follow-up.". Depression and Anxiety 20 (3): 131–138. doi:10.1002/da.20038. PMID 15549689. 
  20. ^ 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. 

External links[edit]