7-Hydroxyropinirole

Pharmaceutical compound From Wikipedia, the free encyclopedia

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]

Other namesSK&F-89124; SKF-89124; SK&F89124; SKF89124; SK&F-89,124; SKF-89,124; SKF-89124A

Drug classDopamine receptor agonist; Dopamine D₂-like receptor agonist

ATC code

None

CAS Number

81654-62-8

Quick facts Clinical data, Other names ...

7-Hydroxyropinirole
Clinical data

Other names	SK&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
IUPAC name 4-[2-(dipropylamino)ethyl]-7-hydroxy-1,3-dihydroindol-2-one
CAS Number	81654-62-8
PubChem CID	133741
ChemSpider	117961
UNII	9LD7EVH3Y5
ChEMBL	ChEMBL587
CompTox Dashboard (EPA)	DTXSID60231232
Chemical and physical data
Formula	C₁₆H₂₄N₂O₂
Molar mass	276.380 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES CCCN(CCC)CCC1=C2CC(=O)NC2=C(C=C1)O
InChI 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

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]

References

[1]
Okano H, Yasuda D, Fujimori K, Morimoto S, Takahashi S (February 2020). "Ropinirole, a New ALS Drug Candidate Developed Using iPSCs". Trends in Pharmacological Sciences. 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]
Hieble JP, Sulpizio AC, Sarau HM, Flaim KE, Blumberg AL, McCafferty JP, et al. (1989). "SK&F 89124, a potent and selective agonist at prejunctional dopamine receptors". Fundamental & Clinical Pharmacology. 3 (6): 621–642. doi:10.1111/j.1472-8206.1989.tb00464.x. PMID 2575569.
[3]
Reavill C, Boyfield I, Coldwell M, Nelson P (September 2000). "Comparative pharmacological study of ropinirole (SKF-101468) and its metabolites in rats". The Journal of Pharmacy and Pharmacology. 52 (9): 1129–1135. doi:10.1211/0022357001774895. PMID 11045894.
[4]
Ramji JV, Keogh JP, Blake TJ, Broom C, Chenery RJ, Citerone DR, et al. (March 1999). "Disposition of ropinirole in animals and man". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 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]
Contin M, Riva R, Albani F, Baruzzi A (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 JP (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". Journal of Pharmaceutical Sciences. 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". Clinical Pharmacokinetics. 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]
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". Computer Methods and Programs in Biomedicine. 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". Journal of Medicinal Chemistry. 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". Journal of Medicinal Chemistry. 28 (10): 1533–1536. doi:10.1021/jm00148a028. PMID 4045928.
[12]
Eden RJ, Costall B, Domeney AM, Gerrard PA, Harvey CA, Kelly ME, et al. (January 1991). "Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist". Pharmacology, Biochemistry, and Behavior. 38 (1): 147–154. doi:10.1016/0091-3057(91)90603-y. PMID 1673248.

7-Hydroxyropinirole

See also

References

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