Pharmacokinetics and metabolism of (<i>R</i>,<i>R</i>)-methoxyfenoterol in rat

Siluk, Danuta; Mager, Donald E.; Kim, Hee Seung; Wang, Yan; Furimsky, Anna; Ta, Amy; Iyer, Lalitha; Green, Carol E.; Wainer, Irving W.

doi:10.3109/00498250903434533

Cited by 6 publications

(6 citation statements)

References 13 publications

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“…We have previously established the pharmacokinetic profile and effective dose of MNF in the rat [43] and demonstrated the effectiveness of MNF as an anticancer drug in cells and xenograft models [44]. Moreover, MNF was found to effectively block GPR55 signaling in tumor cells [21].…”

Section: Discussionmentioning

confidence: 99%

Selective GPR55 antagonism reduces chemoresistance in cancer cells

Singh

Bernier

Wainer

2016

Pharmacological Research

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G protein-coupled receptor 55 (GPR55) possesses pro-oncogenic activity and its function can be competitively inhibited with (R,R’)-4’-methoxy-1-naphthylfenoterol (MNF) through poorly defined signaling pathways. Here, the anti-tumorigenic effect of MNF was investigated in the human pancreatic cancer cell line, PANC-1, by focusing on the expression of known cancer biomarkers and the expression and function of multidrug resistance (MDR) exporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Incubation of PANC1 cells with MNF (1μM) for 24 h significantly decreased EGF receptor, pyruvate kinase M2 (PKM2), and β-catenin protein levels and was accompanied by significant reduction in nuclear accumulation of HIF-1α and the phospho-active forms of PKM2 and β-catenin. Inhibition of GPR55 with either MNF or the GPR55 antagonist CID 16020046 lowered the amount of MDR proteins in total cellular extracts while diminishing the nuclear expression of Pgp and BCRP. There was significant nuclear accumulation of doxorubicin in PANC-1 cells treated with MNF and the pre-incubation with MNF increased the cytotoxicity of doxorubicin and gemcitabine in these cells. Potentiation of doxorubicin cytotoxicity by MNF was also observed in MDA-MB-231 breast cancer cells and U87MG glioblastoma cells, which express high levels of GPR55. The data suggest that inhibition of GPR55 activity produces antitumor effects via attenuation of the MEK/ERK and PI3K-AKT pathways leading to a reduction in the expression and function of MDR proteins.

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Section: Discussionmentioning

confidence: 99%

Selective GPR55 antagonism reduces chemoresistance in cancer cells

Singh

Bernier

Wainer

2016

Pharmacological Research

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“…5 In addition, in the rat, the oral bioavailability of ( R , R ′)- 2 is 3-fold higher than that of ( R , R ′)- 1 , indicating that the substitution of a 4′-methoxy moiety reduced presystemic glucuronidation. 8 Initial studies using the previously described procedures 1,3,5 demonstrated that ( R , R ′)- 64 has no activity in the cardiomyocyte contractility model and effectively inhibits the proliferation of 1321N1 astrocytoma cells with an IC 50 of 1.5 nM (unpublished data). The data suggest that ( R , R ′)- 64 and the COMFA{[ 3 H]-( R , R ′)- 2 } model can be used for the design and optimization of orally available anti-cancer agents which have no cardiovascular effects.…”

Section: Discussionmentioning

confidence: 99%

Comparative molecular field analysis of fenoterol derivatives interacting with an agonist-stabilized form of the β2-adrenergic receptor

Płazińska¹,

Pająk²,

Rutkowska³

et al. 2014

Bioorganic & Medicinal Chemistry

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The β2-adrenergic receptor (β2-AR) agonist [3H]-(R,R′)-methoxyfenoterol was employed as the marker ligand in displacement studies measuring the binding affinities (Ki values) of the stereoisomers of a series of 4′-methoxyfenoterol analogs in which the length of the alkyl substituent at α′ position was varied from 0 to 3 carbon atoms. The binding affinities of the compounds were additionally determined using the inverse agonist [3H]-CGP-12177 as the marker ligand and the ability of the compounds to stimulate cAMP accumulation, measured as EC50 values, were determined in HEK293 cells expressing the β2-AR. The data indicate that the highest binding affinities and functional activities were produced by methyl and ethyl substituents at the α′ position. The results also indicate that the Ki values obtained using [3H]-(R,R′)-methoxyfenoterol as the marker ligand modeled the EC50 values obtained from cAMP stimulation better than the data obtained using [3H]-CGP-12177 as the marker ligand. The data from this study was combined with data from previous studies and processed using the Comparative Molecular Field Analysis approach to produce a CoMFA model reflecting the binding to the β2-AR conformation probed by [3H]-(R,R′)-4′-methoxyfenoterol. The CoMFA model of the agonist-stabilized β2-AR suggests that the binding of the fenoterol analogs to an agonist-stabilized conformation of the β2-AR is governed to a greater extend by steric effects than binding to the [3H]-CGP-12177-stabilized conformation(s) in which electrostatic interactions play a more predominate role.

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“…and oral administration to the rat. 7 The data demonstrated that after oral administration, (R,R)-MF had decreased clearance, increased half-life, and increased area under the curve relative to (R,R)-Fen and, after i.v. administration, a significantly higher systemic exposure.…”

mentioning

confidence: 94%

“…The potential advantages of this approach were supported by the results from an initial study comparing the plasma profiles of ( R , R ′)‐Fen and ( R , R ′)‐MF obtained after i.v. and oral administration to the rat . The data demonstrated that after oral administration, ( R , R ′)‐MF had decreased clearance, increased half‐life, and increased area under the curve relative to ( R , R ′)‐Fen and, after i.v.…”

Section: Introductionmentioning

confidence: 99%

The Stereoselective Sulfate Conjugation of 4′‐Methoxyfenoterol Stereoisomers by Sulfotransferase Enzymes

et al. 2012

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The presystemic sulfate conjugation of the stereoisomers of 4-methoxyfenoterol, (R,R)-MF, (S,S)-MF, (R,S)-MF, and (S,R)-MF, was investigated using commercially available human intestinal S9 fractions, a mixture of sulfotransferase (SULT) enzymes. The results indicate that the sulfation was stereospecific and that an S-configuration at the β-OH carbon of the MF molecule enhanced the maximal formation rates with (S,R)-MF > (S,S)-MF > (R,S)-MF ≈ (R,R)-MF, and competition studies demonstrated that (S,R)-MF is an effective inhibitor of (R,R)-MF sulfation (IC50 = 60 µM). In addition, the results from a cDNA-expressed human SULT isoform screen indicated that SULT1A1, SULT1A3, and SULT1E1 can mediate the sulfation of all four MF stereoisomers. Previously published molecular models of SULT1A3 and SULT1A1 were used in docking simulations of the MF stereoisomers using Molegro Virtual Docker. The models of the MF-SULT1A3 and MF-SULT1A1 complexes indicate that each of the two chiral centers of MF molecule plays a role in the observed relative stabilities. The observed stereoselectivity is the result of multiple hydrogen bonding interactions and induced conformational changes within the substrate-enzyme complex. In conclusion, the results suggest that a formulation developed from a mixture of (R,R)-MF and (S,R)-MF may increase the oral bioavailability of (R,R)-MF.

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Pharmacokinetics and metabolism of (R,R)-methoxyfenoterol in rat

Cited by 6 publications

References 13 publications

Selective GPR55 antagonism reduces chemoresistance in cancer cells

Selective GPR55 antagonism reduces chemoresistance in cancer cells

Comparative molecular field analysis of fenoterol derivatives interacting with an agonist-stabilized form of the β2-adrenergic receptor

The Stereoselective Sulfate Conjugation of 4′‐Methoxyfenoterol Stereoisomers by Sulfotransferase Enzymes

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