Ropinirole

Ropinirole
Systematic (IUPAC) name
4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one
Clinical data
Trade names Requip
AHFS/Drugs.com monograph
MedlinePlus a698013
  • C
  • ℞ (Prescription only)
Oral
Pharmacokinetic data
Bioavailability 50%[1]
Metabolism Hepatic (CYP1A2)[1]
Half-life 5-6 hours[1]
Identifiers
91374-21-9 Yes
N04BC04
PubChem CID 5095
DrugBank DB00268 Yes
ChemSpider 4916 Yes
UNII 030PYR8953 Yes
KEGG D08489 Yes
ChEBI CHEBI:8888 Yes
ChEMBL CHEMBL589 Yes
Chemical data
Formula C16H24N2O
260.375 g/mol
 Yes (what is this?)  (verify)

Ropinirole (INN; trade names Requip, Repreve, Ronirol, Adartrel) is a dopamine agonist of the non-ergoline class of medications. It is manufactured by GlaxoSmithKline (GSK), Cipla, Dr. Reddy's Laboratories and Sun Pharmaceutical. It is used in the treatment of Parkinson's disease and restless legs syndrome (RLS). Ropinirole is one of three medications approved by the FDA to treat RLS, the other two being pramipexole (Mirapex) and gabapentin enacarbil (Horizant). The discovery of the drug's utility in RLS has been used as an example of successful drug repurposing.[2]

Ropinirole's patent expired in May 2008, and the drug is now available in generic form.[3]

Medical uses

Ropinirole is prescribed for mainly Parkinson's disease, RLS and extrapyramidal symptoms. It can also reduce the side effects caused by selective serotonin reuptake inhibitors, including Parkinsonism syndrome as well as sexual dysfunction and erectile dysfunction caused by either SSRIs[4] or antipsychotics.

Dosage

Ropinirole in the Requip form is available in various preparations, ranging from a 0.25 mg tablet to a 5 mg tablet. The primary reason is dose titration. This implies that the person taking Requip has to closely interact and communicate with the primary care physician with regard to how much should actually be taken by the patient.

For Parkinson's disease, the maximum recommended dose is 24 mg per day, taken in three separate doses spread throughout the day. The maximum dose recommendations of ropinirole for subjects with end stage renal disease (ESRD) should be reduced by 25% compared with those recommended for subjects with normal renal function. A 25% dose reduction represents a more straightforward dosage regimen in terms of available tablet strength, compared with a 30% dose reduction.[5]

For RLS, the maximum recommended dose is 4 mg per day, taken 1 to 3 hours before bedtime. A 52-week open label study had a mean dosage of 1.90 mg, once daily 1 to 3 hours before bedtime.[6]

Pharmacology

Ropinirole acts as a D2, D3, and D4 dopamine receptor agonist with highest affinity for D2. It is weakly active at the 5-HT2, and α2 receptors and is said to have virtually no affinity for the 5-HT1, GABA, mAChRs, α1, and β-adrenoreceptors.[7]

Ropinirole is metabolized primarily by cytochrome P450 CYP1A2 to form two metabolites; SK&F-104557 and SK&F-89124, both of which are renally excreted,[5] and at doses higher than clinical, is also metabolized by CYP3A4. At doses greater than 24 mg, CYP2D6 may be inhibited, although this has only been tested in vitro.[1]

Side effects

Ropinirole can cause nausea, dizziness, hallucinations, orthostatic hypotension, and sudden sleep attacks during the daytime. Unusual side effects specific to D3 agonists such as ropinirole and pramipexole can include hypersexuality, punding and compulsive gambling, even in patients without a history of these behaviours.[8]

Lawsuits

In November 2012, GlaxoSmithKline was ordered by a Rennes appeals court to pay Frenchman Didier Jambart 197,000 euros ($255,824); Jambart had taken ropinirole from 2003 to 2010 and exhibited risky hypersexual behavior and gambled excessively until stopping the Parkinson's treatment.[9]

Synthesis

Ropinirole synthesis: G. Gallagher, Jr., U.S. Patent 4,452,808 (1984 to Smithkline Beckman Corporation); idem et al., [10]

The sequence for preparing this agent starts with the homologation of the carboxylic acid in (). The acid is thus reduced to the carbinol () by means of diborane. The hydroxyl is thus next converted to the mesylate in the usual way and that displaced with cyanide. Hydrolysis of the resulting nitrile gives the resulting arylacetic acid (). The acid chloride from that acid is then taken on to the amide () by rxn with dipropylamine. Reduction of the amide with diborane completes the synthesis of the sidechain, affording the amine (). Condensation of the transient anion, from removal of a benzylic proton, with ethyl oxalate gives the chain-extented glyoxylate ester (). Saponification of the ester with NaOH followed by decarboxylation of the resulting α-ketoacid gives (). The nitro group is hydrogenated to give the transient amine (). Intramolecular cyclization of the amine and acid function then occurs to give the indolone lactam, ropinirole.

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 Tompson, Debra J. et al. (2007). "Steady-State Pharmacokinetic Properties of a 24-Hour Prolonged-Release Formulation of Ropinirole: Results of Two Randomized Studies in Patients with Parkinson’s Disease". Clinical Pharmacokinetics 29 (12): 2654–66. doi:10.1016/j.clinthera.2007.12.010. PMID 18201581.
  2. ↑ Lipp, Elizabeth (2008-08-01). "Novel Approaches to Lead Optimization". Genetic Engineering & Biotechnology News. Drug Discovery 28 (14) (Mary Ann Liebert). p. 20. ISSN 1935-472X. Retrieved 2008-09-28. Note: The opinion that ropinirole's use in RLS was a successful example of drug repurposes was reported as being that of Josef Scheiber, a post-doctoral fellow at the Novartis Institutes for BioMedical Research.
  3. ↑ New pharmaceutical products: Ceftriaxon-Rocephin, Granisetron-Kytril, Ipratropium-Albuterol
  4. ↑ Clinical trial number NCT00334048 at ClinicalTrials.gov - "Treating Sexual Dysfunction From SSRI Medication: a Study Comparing Requip CR to Placebo"
  5. ↑ 5.0 5.1 An open-label, parallel-group, repeat-dose study to investigate the effects of end-stage renal disease and haemodialysis on the pharmacokinetics of ropinirole | Authors: Debra J. Tompson, Deborah Hewens, Nancy Earl, David Oliveira, Jorg Taubel, Suzanne Swan, Luigi Giorgi | 13th International Congress of Parkinson’s Disease and Movement Disorders, Paris, France, June 7–11, 2009
  6. ↑ Garcia-Borreguero D, Grunstein R, Sridhar G et al. (November 2007). "A 52-week open-label study of the long-term safety of ropinirole in patients with restless leg syndrome". Sleep Med. 8 (7–8): 742–52. doi:10.1016/j.sleep.2006.09.009. PMID 17512789.
  7. ↑ Eden, R. J. et al. (1991). "Preclinical Pharmacology of Ropinirole (SK&F 101468-A) a Novel Dopamine D 2 Agonist". Pharmacology Biochemistry & Behavior 38: 147–154. doi:10.1016/0091-3057(91)90603-Y.
  8. ↑ Bostwick JM, Hecksel KA, Stevens SR, Bower JH, Ahlskog JE (2009). "Frequency of new-onset pathologic compulsive gambling or hypersexuality after drug treatment of idiopathic Parkinson disease". Mayo Clinic Proceedings 84 (4): 310–6. doi:10.4065/84.4.310. PMC 2665974. PMID 19339647.
  9. ↑ Wong, Curtis (2012-11-29). "Court Rules Parkinson's Drug Turned Straight Patient Into A Gay Sex Addict". Huffington Post.
  10. ↑ Gallagher, G.; Lavanchy, P. G.; Wilson, J. W.; Hieble, J. P.; Demarinis, R. M. (1985). "4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone: A prejunctional dopamine receptor agonist". Journal of Medicinal Chemistry 28 (10): 1533. doi:10.1021/jm00148a028. PMID 4045928.

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