7-Hydroxyropinirole

Last updated
7-Hydroxyropinirole
7-Hydroxyropinirole.svg
Clinical data
Other namesSK&F-89124; SKF-89124; SK&F89124; SKF89124; SK&F-89,124; SKF-89,124; SKF-89124A
Drug class Dopamine receptor agonist; Dopamine D2-like receptor agonist
ATC code
  • None
Identifiers
  • 4-[2-(dipropylamino)ethyl]-7-hydroxy-1,3-dihydroindol-2-one
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C16H24N2O2
Molar mass 276.380 g·mol−1
3D model (JSmol)
  • CCCN(CCC)CCC1=C2CC(=O)NC2=C(C=C1)O
  • InChI=1S/C16H24N2O2/c1-3-8-18(9-4-2)10-7-12-5-6-14(19)16-13(12)11-15(20)17-16/h5-6,19H,3-4,7-11H2,1-2H3,(H,17,20)
  • Key:PVIICBUWKXYFAA-UHFFFAOYSA-N

7-Hydroxyropinirole (developmental code name SK&F-89124 or SKF-89124) is a dopamine receptor agonist and active metabolite of the antiparkinsonian agent ropinirole (SK&F-101468). [1] [2] [3] It is a major metabolite of ropinirole in rats and dogs but a minor metabolite in mice, monkeys, and humans. [4] [3] In humans, 7-hydroxyropinirole accounts for less than 5% of a dose of ropinirole. [5] Its involvement in ropinirole's effects in humans is unknown. [5]

The drug is described as a highly potent and highly selective dopamine D2-like receptor agonist. [2] It has been reported to be 30-fold more potent than ropinirole as a dopamine D2 receptor agonist in vitro . [6] [7] However, ropinirole and 7-hydroxyropinirole were equipotent in terms of antiparkinsonian activity in rodents in vivo . [3]

7-Hydroxyropinirole is said to be rapidly glucuronidated in humans. [8] In addition, 7-hydroxyropinirole has reduced capacity to cross the blood–brain barrier than ropinirole. [9] This is due to its hydroxyl group, which increases it polarity and reduces its lipophilicity. [9] The log P of ropinirole is 2.46, whereas that of 7-hydroxyropinirole is 2.17. [9]

7-Hydroxyropinirole was first described in the scientific literature by 1983. [10] Subsequently, ropinirole was described in 1985. [1] [11] [12]

See also

References

  1. 1 2 Okano H, Yasuda D, Fujimori K, Morimoto S, Takahashi S (February 2020). "Ropinirole, a New ALS Drug Candidate Developed Using iPSCs". Trends Pharmacol Sci. 41 (2): 99–109. doi:10.1016/j.tips.2019.12.002. PMID   31926602. Before ROPI was first reported in 1985 [27], 7-hydroxyropinirole was identified as a highly potent dopamine agonist [28,29]. 7-Hydroxyropinirole has also been identified as a metabolite of ROPI in humans. [...] N,N-di-n-Propyldopamine is a lipophilic derivative of dopamine. By conversion of the monocyclic ring of N,N-di-n-propyldopamine to a bicyclic oxindole skeleton (bioisostere of phenol), 7-hydroxyropinirole was developed. Surprisingly, compared with that of N,N-di-npropyldopamine, the EC50 of 7-hydroxyropinirole for the dopamine D2 receptor (D2R) was greatly improved. ROPI does not have a 7-hydroxy group and its EC50 for D2R is higher than that of N,N-di-n-propyldopamine; nevertheless ROPI was ultimately selected as a clinical drug candidate.
  2. 1 2 Hieble JP, Sulpizio AC, Sarau HM, Flaim KE, Blumberg AL, McCafferty JP, Zeid RL (1989). "SK&F 89124, a potent and selective agonist at prejunctional dopamine receptors". Fundam Clin Pharmacol. 3 (6): 621–642. doi:10.1111/j.1472-8206.1989.tb00464.x. PMID   2575569.
  3. 1 2 3 Reavill C, Boyfield I, Coldwell M, Nelson P (September 2000). "Comparative pharmacological study of ropinirole (SKF-101468) and its metabolites in rats". J Pharm Pharmacol. 52 (9): 1129–1135. doi:10.1211/0022357001774895. PMID   11045894.
  4. ↑ Ramji JV, Keogh JP, Blake TJ, Broom C, Chenery RJ, Citerone DR, Lewis VA, Taylor AC, Yeulet SE (March 1999). "Disposition of ropinirole in animals and man". Xenobiotica. 29 (3): 311–325. doi:10.1080/004982599238696. PMID   10219970. In both animals and man, ropinirole was extensively metabolized. In the rat, the major metabolic pathway was via hydroxylation of the aromatic ring to form 7-hydroxy ropinirole. In mouse, monkey and man, the major pathway was via N-depropylation. The N-despropyl metabolite was metabolized further to form 7-hydroxy and carboxylic acid derivatives. Metabolites formed in all species were generally metabolized further by glucuronidation. 7-Hydroxy ropinirole is the only metabolite of ropinirole previously shown to possess significant dopamine agonist activity in vivo. [...] Brain extracts were shown to contain ropinirole and its 7-hydroxy metabolite (SK&F-89124 ; Figure 2). [...] In rat, the major metabolic pathway was via hydroxylation of the aromatic ring to form 7-hydroxy ropinirole (SK&F-89124). In mouse, monkey and man, the major pathway was via N-depropylation to form SK&F-104557, which was further metabolized, to a limited extent, to 7-hydroxy SK&F-104557 (SK&F-96990) and a carboxylic acid derivative of SK&F-104557 (SK&F-97930). Metabolites formed by either pathway were then generally metabolized further by glucuronidation in all species. SK&F-89124 is the only metabolite of ropinirole shown to possess significant dopamine agonist activity in an in vivo model of Parkinson's disease (Reavill et al., unpublished data).
  5. 1 2 Contin, Manuela; Riva, Roberto; Albani, Fiorenzo; Baruzzi, Agostino (2000). "Pharmacokinetic Optimisation of Dopamine Receptor Agonist Therapy for Parkinson??s Disease". CNS Drugs. 14 (6): 439–455. doi:10.2165/00023210-200014060-00003. ISSN   1172-7047. The major metabolic pathway in humans is via N-depropylation;[55] the N-despropyl metabolite accounts for 35 to 40% of the oral dose in human urine. 7-hydroxy ropinirole, the only metabolite of ropinirole that is thought to have significant dopamine agonist activity in vivo, [55] accounts for less than 5% of the dose. The potential contribution of 7-hydroxy ropinirole to the clinical effects of the parent drug is unknown.
  6. ↑ Hieble, J. Paul (1987). "Chapter 11 Peripheral Actions of Dopamine Receptor Agonists". Annual Reports in Medicinal Chemistry. Vol. 22. Elsevier. pp. 107–116. doi:10.1016/s0065-7743(08)61159-8. ISBN   978-0-12-040522-0. ISSN   0065-7743. SK&F 101468 is hydroxylated vivo to form SK&F 89124, which is 30-fold more potent as a DA2 agonist (77); hence, although SK&F 101468 has intrinsic agonist activity at the DA2 receptor, being only two-fold less potent than dopamine as an inhibitor of adrenergic neurotransmission in the isolated rabbit ear artery (76), the majority of its in vivo activity may result from an active metabolite.
  7. ↑ Mico BA, Swagzdis JE, Federowicz DA, Straub K (October 1986). "Functional group metabolism of dopamine-2 agonists: conversion of 4-(2-di-n-propylaminoethyl)-2-(3H)-indolone to 4-(2-di-n-propylaminoethyl)-7-hydroxy-2-(3H)-indolone". J Pharm Sci. 75 (10): 929–933. Bibcode:1986JPhmS..75..929M. doi:10.1002/jps.2600751003. PMID   3795021. 4-(2-Di-n-propylaminoethyl)-7-hydroxy-2-(3~)-indolone was found in the plasma of rats, dogs, and monkeys treated with 3. As a D2-agonist, 1 is 30 times more potent than 3 in in vitro studies.1.3 The metabolism of 3 to 1 may contribute to the in vivo pharmacologic effect of 3. In dogs and monkeys (Figs. 5 and 6) the concentrations of 1 are about 10-fold lower than those of 3 and decline in parallel with 3.
  8. ↑ Kaye CM, Nicholls B (October 2000). "Clinical pharmacokinetics of ropinirole". Clin Pharmacokinet. 39 (4): 243–254. doi:10.2165/00003088-200039040-00001. PMID   11069211. Most of the absorbed dose of ropinirole is cleared by metabolism in the liver, with only 10% of the administered dose being excreted as unchanged ropinirole.[35,42] The main metabolite of ropinirole (32 to 45% of the dose) is the N-despropyl metabolite SK&F 104557 (fig. 1).[35,43] The glucuronide of the metabolite SK&F 89124 and the carboxylic acid metabolite SK&F 97930 both represent about 10% of the administered dose. Neither of these metabolites is pharmacologically active; SK&F 89124 has some activity but is rapidly glucuronidated, and so it circulates at only low concentrations.[44] Therefore, all of the pharmacological activity achieved by orally administered ropinirole can be attributed to the parent molecule.
  9. 1 2 3 Chen Y, Zhu QJ, Pan J, Yang Y, Wu XP (September 2009). "A prediction model for blood-brain barrier permeation and analysis on its parameter biologically". Comput Methods Programs Biomed. 95 (3): 280–287. doi:10.1016/j.cmpb.2009.03.006. PMID   19473718. Three pairs of similar compounds collected from the dataset used in this paper are shown in Table 4. [...] The difference between SKF101468 and SKF89124 is shown in Fig. 13. The hydroxy group reduces logP and increases PSA, the influences of the hydroxy group makes logBB decrease.
  10. ↑ Huffman WF, Hall RF, Grant JA, Wilson JW, Hieble JP, Hahn RA (July 1983). "4-(Aminoalkyl)-7-hydroxy-2(3H)-indolones, a novel class of potent presynaptic dopamine receptor agonists". J Med Chem. 26 (7): 933–935. doi:10.1021/jm00361a001. PMID   6306238.
  11. ↑ Gallagher G, Lavanchy PG, Webster CA, Wilson JW, Hieble JP, DeMarinis RM (October 1985). "4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone: a prejunctional dopamine receptor agonist". J Med Chem. 28 (10): 1533–1536. doi:10.1021/jm00148a028. PMID   4045928.
  12. ↑ Eden RJ, Costall B, Domeney AM, Gerrard PA, Harvey CA, Kelly ME, Naylor RJ, Owen DA, Wright A (January 1991). "Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist". Pharmacol Biochem Behav. 38 (1): 147–154. doi:10.1016/0091-3057(91)90603-y. PMID   1673248.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.