Characterization of rat liver microsomal metabolites of AM‐630, a potent cannabinoid receptor antagonist, by high‐performance liquid chromatography/electrospray ionization tandem mass spectrometry

Zhang, Qiang; Ma, Peng; Wang, Weiqun; Cole, Richard B.; Wang, Guangdi

doi:10.1002/jms.640

Cited by 18 publications

(21 citation statements)

References 16 publications

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“…Monohydroxylation occurs mainly on position 2 of the morpholine group, which results in opening of the ring system. Hydroxylation on morpholino rings attached to heterocycles has been reported previously and N-oxidations have also been described (Langner et al, 1993;Baker et al, 1999;Huskey et al, 2004;Zhang et al, 2004;Zhao et al, 2004). Our study suggests that the modest bioavailability of NU7026 is not due to first pass metabolism as the relative proportion of administered dose present as parent or metabolites are similar after i.v., i.p.…”

Section: Discussionsupporting

confidence: 81%

Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026

et al. 2005

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In this study we investigated the in vitro time dependence of radiosensitisation, pharmacokinetics and metabolism of NU7026, a novel inhibitor of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). At a dose of 10 mM, which is nontoxic to cells per se, a minimum NU7026 exposure of 4 h in combination with 3 Gy radiation is required for a significant radiosensitisation effect in CH1 human ovarian cancer cells. Following intravenous administration to mice at 5 mg kg À1 , NU7026 underwent rapid plasma clearance (0.108 l h À1 ) and this was largely attributed to extensive metabolism. Bioavailability following interperitoneal (i.p.) and p.o. administration at 20 mg kg À1 was 20 and 15%, respectively. Investigation of NU7026 metabolism profiles in plasma and urine indicated that the compound undergoes multiple hydroxylations. A glucuronide conjugate of a bis-hydroxylated metabolite represented the major excretion product in urine. Identification of the major oxidation site as C-2 of the morpholine ring was confirmed by the fact that the plasma clearance of NU7107 (an analogue of NU7026 methylated at C-2 and C-6 of the morpholine ring) was four-fold slower than that of NU7026. The pharmacokinetic simulations performed predict that NU7026 will have to be administered four times per day at 100 mg kg À1 i.p. in order to obtain the drug exposure required for radiosensitisation.

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Section: Discussionsupporting

confidence: 81%

Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026

et al. 2005

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“…Unlike aminoalkylindoles, in which extensive hydroxylations were observed at various sites of the parent compounds (Zhang et al, 2002(Zhang et al, , 2004, the only site vulnerable to metabolic activities appears to be the terminal group of the 3-substituent on the pyrazole ring (Fig. 1), whereas no metabolic modification has been detected at other sites of the diarylpyrazoles.…”

Section: Discussionmentioning

confidence: 97%

In Vitro Metabolism of Diarylpyrazoles, a Novel Group of Cannabinoid Receptor Ligands

Zhang

Ma²,

Wang³

et al. 2005

Drug Metabolism and Disposition

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There has been no report on the metabolism of any of the diarylpyrazoles, and it is unknown whether their metabolites retain any receptor binding properties. We report a study of the in vitro metabolisms of three diarylpyrazole analogs, SR141716A, AM251, and AM281, in rat liver microsomes. The metabolic profile was obtained using high-performance liquid chromatography with UV and mass spectrometry detectors. All identified metabolites are characterized by structural modifications on the terminal group of the 3-substituent. Thus, three pairs of isomeric metabolites were identified from the microsomal incubation of SR141716A; these metabolites are products of hydroxylation, hydroxylation followed by dehydration, and a combination of the two. For AM251, only four metabolic products were detected, with two resulting from monohydroxylation of the piperidine ring and the other two being products of dehydration of the first pair of metabolites. For AM281, in which the terminal group of the 3-substituent is a morpholine ring, dehydration of the first two metabolites yielded a single third metabolite due to only one possible position for the carbon-carbon double bond on the morpholinyl ring.

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“…One indole derivative, AM1241, (49) with K i = 3.4 ± 0.5 nM at the CB 2 receptor and K i = 280 ± 41 nM at the CB 1 Two studies of the in vitro metabolism of cannabimimetic indoles have been carried out by Zhang et al [54,55]. Both of these studies employed rat liver microsomes, and the metabolites were characterized by a combination of mass spectrometry and NMR spectroscopy.…”

Section: As Indicated Inmentioning

confidence: 99%

“…The minor products included two monohydroxy compounds and metabolites derived by oxidation of the morpholine ring. The second study was an investigation of the metabolism of AM630 (50), in which the metabolites were characterized by mass spectrometry [55]. A total of 17 metabolites were identified, which included cleavage of the methyl ether, aromatic hydroxylation and a variety of products resulting from oxidation of the morpholine ring, with and without ether cleavage.…”

Section: As Indicated Inmentioning

confidence: 99%

Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes

Huffman¹,

Padgett²

2005

CMC

223

102

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During the development of new nonsteroidal anti-inflammatory agents, it was discovered that 1-aminoalkyl-3-aroylindoles have affinity for the cannabinoid brain (CB(1)) receptor. This has led to the development of over 100 cannabimimetic aminoalkylindoles, and the development of SAR for these compounds. Later work demonstrated that the aminoalkyl moiety was not necessary, and could be replaced by a four- to six-membered alkyl chain without loss of affinity. Investigation of these indoles led to the discovery of a CB(2) selective ligand, 3-(1-naphthoyl)-N-propylindole. Subsequent work has provided several additional CB(2) selective indoles. On the basis of a proposed pharmacophore for the cannabimimetic indoles, a series of pyrroles and indenes were developed, some of which are potent cannabinoids. SAR for several series of pyrroles have been developed. Two groups have described cannabimimetic indenes, which have been employed as rigid models for the receptor interactions of cannabimimetic indoles with the CB(1) receptor. There is some evidence that the indoles bind to a somewhat different site on the receptor than traditional cannabinoids, and interact with the receptor primarily by aromatic stacking.

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Characterization of rat liver microsomal metabolites of AM‐630, a potent cannabinoid receptor antagonist, by high‐performance liquid chromatography/electrospray ionization tandem mass spectrometry

Cited by 18 publications

References 16 publications

Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026

Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026

In Vitro Metabolism of Diarylpyrazoles, a Novel Group of Cannabinoid Receptor Ligands

Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes

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