Research Topics
Species | John CashmanSummaryAffiliation: Human BioMolecular Research Institute Country: USA Publications
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Publications
Human flavin-containing monooxygenase (form 3): polymorphisms and variations in chemical metabolismJohn R Cashman
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
Pharmacogenomics 3:325-39. 2002..Heterogeneity in the relative frequencies of single and multiple site alleles, haplotypes and genotypes of the human FMO3 amongst various ethnic groups suggests population differences...- Some distinctions between flavin-containing and cytochrome P450 monooxygenasesJohn R Cashman
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
Biochem Biophys Res Commun 338:599-604. 2005..These properties may provide advantages in drug design, and by incorporating FMO detoxication pathways into drug candidates, more drug-like materials may emerge... - Quantitative analysis of FMO gene mRNA levels in human tissuesJun Zhang
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
Drug Metab Dispos 34:19-26. 2006..e., FMO1 in kidney, FMO2 in lung, FMO3 and FMO5 in adult liver), FMO4 mRNA was observed more broadly at relatively comparable levels in liver, kidney, lung, and small intestine... 
Immunodetection of serum albumin adducts as biomarkers for organophosphorus exposureSigeng Chen
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121
J Pharmacol Exp Ther 344:531-41. 2013....- Identification of human butyrylcholinesterase organophosphate-resistant variants through a novel mammalian enzyme functional screenJun Zhang
Human BioMolecular Research Institute, San Diego, CA 92121, USA
J Pharmacol Exp Ther 343:673-82. 2012..The mammalian functional screening approach can serve as a cornerstone for further optimization and screening for OP-resistant hBChEs for potential therapeutic applications... 
Substituted heteroaromatic compounds: effect on nicotine self-administration in ratsJohn R Cashman
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
Psychopharmacology (Berl) 221:637-48. 2012..e., human cytochrome P-450 2A6, hCYP 2A6) showed inhibition of smoking in humans. However, a comprehensive examination of hCYP 2A6 inhibitors to decrease nicotine self-administration in rats has not been reported...- Curcumins promote monocytic gene expression related to β-amyloid and superoxide dismutase clearanceJ R Cashman
Human BioMolecular Research Institute, San Diego, Calif 92121, USA
Neurodegener Dis 10:274-6. 2012..Recursive medicinal chemistry was applied to identify compounds that stimulate the innate immune system for use in the clearance of Aβ in AD and the reversal of neuroinflammation and defective SOD-1 accumulation in ALS... - Transient trimethylaminuria related to menstruationMakiko Shimizu
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194 8543, Japan
BMC Med Genet 8:2. 2007.... - The implications of polymorphisms in mammalian flavin-containing monooxygenases in drug discovery and developmentJohn R Cashman
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
Drug Discov Today 9:574-81. 2004..Examples of FMO allelic variation and splicing variants suggest that these genetic mutations could contribute to the interindividual and interethnic variability of FMO-mediated metabolism... - Role of flavin-containing monooxygenase in drug developmentJohn R Cashman
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
Expert Opin Drug Metab Toxicol 4:1507-21. 2008..However, I include discussion of these areas to stimulate further work and invite further discussion... - Immune defects in Alzheimer's disease: new medications developmentJohn R Cashman
Human BioMolecular Research Institute, San Diego, CA 92121, USA
BMC Neurosci 9:S13. 2008..Bisdemethoxycurcumin appears to enhance immune function in mononuclear cells of AD patients and may provide a novel approach to AD immunotherapy... - Analysis of flavin-containing monooxygenase 3 genotype data in populations administered the anti-schizophrenia agent olanzapineJohn R Cashman
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
Drug Metab Lett 2:100-14. 2008..In female Asian American, allele frequency for FMO3 257 was significantly associated with diagnosis and in males, genotype frequency for FMO3 257 and diagnosis was significantly associated... - Dual inhibitors of phosphodiesterase-4 and serotonin reuptakeJohn R Cashman
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, California 92121, USA
J Med Chem 52:1530-9. 2009..On a molar basis, the antidepressant-like effect of the dual PDE4 inhibitor/SSRI 21 showed a 129-fold increase in in vivo efficacy compared to fluoxetine... - Human flavin-containing monooxygenasesJohn R Cashman
Human BioMolecular Research Institute, San Diego, CA 92121, USA
Annu Rev Pharmacol Toxicol 46:65-100. 2006..Although exhaustive examples are not available, physiological factors can influence FMO function, and this may have implications for the clinical significance of FMO and a role in human disease... - Dynamic medicinal chemistry in the elaboration of morphine-6-glucuronide analogsJohn R Cashman
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, California, 92121
Curr Top Med Chem 5:585-94. 2005..Development of new pain medications for cancer and other diseases based on M6G could provide novel agents that could balance optimal analgesia with a decreased occurrence of adverse side effects... - Inhibition of serotonin and norepinephrine reuptake and inhibition of phosphodiesterase by multi-target inhibitors as potential agents for depressionJohn R Cashman
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
Bioorg Med Chem 17:6890-7. 2009..e., (R)-15 and (S)-15) also inhibited PDE4D2 (i.e., K(i) values of 23 and 45 nM, respectively). Due to their synergistic functional activity, SNRI/PDE4 inhibitors may be effective in treating diseases such as depression... - Stereoselective inhibition of serotonin re-uptake and phosphodiesterase by dual inhibitors as potential agents for depressionJohn R Cashman
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
Bioorg Med Chem 17:337-43. 2009..e., K(i) values of 106 and 253 nM, respectively). Due to the synergistic functional activity, PDE4 inhibitor/SSRIs may be effective in treating diseases such as depression... - Effect of total parenteral nutrition and choline on hepatic flavin-containing and cytochrome P-450 monooxygenase activity in ratsJohn R Cashman
Human BioMolecular Research Institute, San Diego, CA 92121, USA
Drug Metab Dispos 32:222-9. 2004..The clinical relevance of these results is unknown but may be of significance for individuals receiving total parenteral nutrition and those afflicted with trimethylaminuria... - The role of flavin-containing monooxygenases in drug metabolism and developmentJohn R Cashman
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92106, USA
Curr Opin Drug Discov Devel 6:486-93. 2003.... - Inhibition of Bfl-1 with N-aryl maleimidesJohn R Cashman
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, United States
Bioorg Med Chem Lett 20:6560-4. 2010..Inhibitors of Bfl-1 are potential development candidates for anti-cancer therapeutics... - Biochemical and clinical aspects of the human flavin-containing monooxygenase form 3 (FMO3) related to trimethylaminuriaJohn R Cashman
Human BioMolecular Research Institute, San Diego, CA, USA
Curr Drug Metab 4:151-70. 2003..The remarkable progress in the biochemical, genetic, clinical basis for understanding the trimethylaminuria condition is summarized and points to needs in the treatment of individuals suffering from trimethylaminuria... - Interindividual differences of human flavin-containing monooxygenase 3: genetic polymorphisms and functional variationJohn R Cashman
Human BioMolecular Research Institute, San Diego 92121, California
Drug Metab Dispos 30:1043-52. 2002..Human FMO3 may be another example of an environmental gene that participates in a protective mechanism to help humans ward off potentially toxic exposure of chemicals... - Two new polymorphisms of the FMO3 gene in Caucasian and African-American populations: comparative genetic and functional studiesVirginie Lattard
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
Drug Metab Dispos 31:854-60. 2003..Based on the functional activity of the variant FMO3 enzymes, it is likely that population differences exist for compounds primarily metabolized by FMO3... - Novel variants of the human flavin-containing monooxygenase 3 (FMO3) gene associated with trimethylaminuriaMeike S Motika
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
Mol Genet Metab 97:128-35. 2009..In another study, genotyping analysis of a 17 year old female revealed a mutation that caused a frame shift after K415 and resulted in a protein variant with only 486 amino acid residues that was associated with severe TMAu... - Design, chemical synthesis, and biological evaluation of thiosaccharide analogues of morphine- and codeine-6-glucuronideJames M MacDougall
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, California 92121-2804, USA
J Med Chem 47:5809-15. 2004..The in vivo antinociceptive activity of compound 5b was evaluated by the tail flick latency test, giving an ED50 of 2.5 mg/kg... - Synthesis and biological evaluation of alpha- and beta-6-amido derivatives of 17-cyclopropylmethyl-3, 14beta-dihydroxy-4, 5alpha-epoxymorphinan: potential alcohol-cessation agentsSenait Ghirmai
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
J Med Chem 51:1913-24. 2008..The ED 50 of inhibition of 10% ethanol self-administration in trained rats, using operant techniques for 11, was 0.5 mg/kg... - Synthesis and in vitro biological evaluation of a carbon glycoside analogue of morphine-6-glucuronideJames M MacDougall
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121 2804, USA
Bioorg Med Chem Lett 15:1583-6. 2005..Compound 3 was also very stable at pH 2 and pH 7.4, suggesting that 3 possessed properties for sustained duration of action... - Design and synthesis of selective inhibitors of placental alkaline phosphataseMarion Lanier
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121 2804, USA
Bioorg Med Chem 18:573-9. 2010..These selective PLAP inhibitors will provide small molecule probes for the study of the pathophysiological role of PLAP... - Selective benzimidazole inhibitors of the antigen receptor-mediated NF-kappaB activation pathwayKarl J Okolotowicz
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
Bioorg Med Chem 18:1918-24. 2010..A library of analogs was synthesized and the structure-activity relationship and metabolic stability for the series is presented... - Functional activity of the mouse flavin-containing monooxygenase forms 1, 3, and 5Jun Zhang
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
J Biochem Mol Toxicol 21:206-15. 2007..The results revealed unique features for mFMO5, suggesting possible impact on the functional significance of this abundantly expressed FMO5 isoform in both human and mouse liver... - Synthesis and biological evaluation of some 6-arylamidomorphines as analogues of morphine-6-glucuronideJames M MacDougall
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121 2804, USA
Bioorg Med Chem 12:5983-90. 2004..2-0.6 nM). Functional assays showed that compounds 10a-h acted as full mu opioid receptor agonists. The ED(50) of compound 10e.HCl as an analgesic was 12.6 mg/kg in the tail flick latency test in the rat... - 5-substituted, 6-substituted, and unsubstituted 3-heteroaromatic pyridine analogues of nicotine as selective inhibitors of cytochrome P-450 2A6Travis T Denton
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, California 92121, USA
J Med Chem 48:224-39. 2005..We also found a number of compounds to be highly selective for the inhibition of human CYP2A6 versus the other human CYPs examined... - Inhibition of human liver microsomal (S)-nicotine oxidation by (-)-menthol and analoguesJames M MacDougall
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, California 92126, USA
Chem Res Toxicol 16:988-93. 2003..This may be another example of self-medication to obtain the desired effect of nicotine... - Synthesis and pharmacological evaluation of 6-naltrexamine analogs for alcohol cessationSenait Ghirmai
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
Bioorg Med Chem 17:6671-81. 2009..The inhibition of ethanol self-administration in rats trained to self-administer a 10% (w/v) ethanol solution, utilizing operant techniques showed 5-8 to have very potent efficacy (ED(50) values 19-50 microg/kg)... - Synthetic inhibitors of cytochrome P-450 2A6: inhibitory activity, difference spectra, mechanism of inhibition, and protein cocrystallizationJason K Yano
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, California 92121, USA
J Med Chem 49:6987-7001. 2006..The results suggest that inhibitors that compliment the active site features of CYP2A6 can exhibit significant selectivity for CYP2A6 relative to other human liver drug-metabolizing P450s... - Deleterious mutations in the flavin-containing monooxygenase 3 (FMO3) gene causing trimethylaminuriaJun Zhang
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
Pharmacogenetics 13:495-500. 2003..The two deleterious mutations reported herein were rare mutations with estimated allelic frequencies of less than 1%... - Nicotine-related alkaloids and metabolites as inhibitors of human cytochrome P-450 2A6Travis T Denton
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
Biochem Pharmacol 67:751-6. 2004..Our results indicate that the prominent nicotine-related alkaloid beta-nicotyrine present after smoking potently inhibits human CYP2A6... - 2,5-Disubstituted tetrahydrofurans as selective serotonin re-uptake inhibitorsTroy Voelker
Human BioMolecular Research Institute, San Diego, CA 92121, USA
Bioorg Med Chem 17:2047-68. 2009..Acute administration of 32c (10mg/kg), or 32d (10mg/kg) ip tended to decrease the duration of mouse immobility in the FST although the effect was not statistically significant... - Bivalent biogenic amine reuptake inhibitorsKeith Fandrick
Human BioMolecular Research Institute, 5310 Eastgate Mall, 92121, San Diego, CA, USA
Bioorg Med Chem Lett 13:2151-4. 2003..The bivalent ligand 4, comprised of linking an aryltropane by an octamethylene spacer showed high efficacy for the human dopamine transporter and had a discrimination ratio of 130... - Hepatic flavin-containing monooxygenase gene regulation in different mouse inflammation modelsJun Zhang
Human BioMolecular Research Institute, San Diego, California, USA
Drug Metab Dispos 37:462-8. 2009..Unlike cytochrome P450 regulation measured in the same mouse strains, Fmo3 expression was largely refractory to down-regulation in the DSS model of inflammatory colitis... - Chemical biology strategy reveals pathway-selective inhibitor of NF-kappaB activation induced by protein kinase CRanxin Shi
Sanford Burnham Medical Research Institute, La Jolla, San Diego, California 92037, USA
ACS Chem Biol 5:287-99. 2010..Altogether, as a selective chemical inhibitor of the NF-kappaB pathway induced by PKC, CID-2858522 serves as a powerful research tool and may reveal new paths toward therapeutically useful NF-kappaB inhibitors... - Syntheses of 3-carbomethoxy-4-(aryl)piperidines and in vitro and in vivo pharmacological evaluation: identification of inhibitors of the human dopamine transporterXianqi Feng
Human BioMolecular Research Institute, 5310 Eastgate Mall, CA 92121, San Diego, USA
Bioorg Med Chem 11:775-80. 2003..The conclusion is that substantial portions of the cocaine structure can be dissected away to provide compounds with significant binding and reuptake inhibition of the human dopamine transporter... - Human and plant flavin-containing monooxygenase N-oxygenation of amines: detoxication vs. bioactivationJohn R Cashman
Human BioMolecular Research Institute, San Diego, CA 92121, USA
Drug Metab Rev 34:513-21. 2002..However, study of the Arabidopsis FMO-like enzyme may provide considerable insight into the possible role of mammalian FMOs in biogenic amine metabolism... - Chemical synthesis of two series of nerve agent model compounds and their stereoselective interaction with human acetylcholinesterase and human butyrylcholinesteraseNora H Barakat
Human BioMolecular Research Institute, San Diego, California 92121, USA
Chem Res Toxicol 22:1669-79. 2009..The potential of and limitations for using these model compounds in the development of biological therapeutics against nerve agent toxicity are also discussed... - Flavin-containing monooxygenase 3 and human diseaseMeike S Motika
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA
Expert Opin Drug Metab Toxicol 3:831-45. 2007.... - Investigation of structure and function of a catalytically efficient variant of the human flavin-containing monooxygenase form 3Tímea Borbás
Human BioMolecular Research Institute, San Diego, CA 92121, USA
Drug Metab Dispos 34:1995-2002. 2006..A molecular model of human FMO3 was also constructed to help explain the results. The increase in catalytic efficiency observed for Pro360 in human FMO3 was also observed when the His of FMO1 was replaced by Pro at loci 360... - Nerve agent analogues that produce authentic soman, sarin, tabun, and cyclohexyl methylphosphonate-modified human butyrylcholinesteraseCynthia Gilley
Human BioMolecular Research Institute, San Diego, California 92121, USA
Chem Res Toxicol 22:1680-8. 2009..However, the soman and sarin thiomethyl compounds yielded two types of adducts, one of which was thiomethyl phosphonate, a modification not found after treatment with authentic soman and sarin... - Direct detection of the hydrolysis of nerve agent model compounds using a fluorescent probeXueying Zheng
Human BioMolecular Research Institute, San Diego, CA 92121, United States
Chem Biol Interact 187:330-4. 2010.... - Alternative processing events in human FMO genesVirginie Lattard
Human BioMolecular Research Institute, San Diego, California, USA
Mol Pharmacol 65:1517-25. 2004..It is not clear whether these FMO splice variants can oxygenate other substrates, including those that remain to be discovered... - Effect of genetic variants of the human flavin-containing monooxygenase 3 on N- and S-oxygenation activitiesMakiko Shimizu
Showa Pharmaceutical University, 3 3165 Higashi tamagawa Gakuen, Machida, Tokyo 194 8543, Japan
Drug Metab Dispos 35:328-30. 2007..Genetic polymorphism in the human FMO3 gene might lead to unexpected changes of catalytic efficiency for N- and S-oxygenation of xenobiotics and endogenous materials... - Effects of the dietary supplements, activated charcoal and copper chlorophyllin, on urinary excretion of trimethylamine in Japanese trimethylaminuria patientsHiroshi Yamazaki
Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, N12W6, Kita ku, Sapporo 060 0812, Japan
Life Sci 74:2739-47. 2004..several weeks) than those observed for activated charcoal. The results suggest that the daily intake of charcoal and/or copper chlorophyllin may be of significant use in improving the quality of life of individuals suffering from TMAU... - Stop codon mutations in the flavin-containing monooxygenase 3 (FMO3) gene responsible for trimethylaminuria in a Japanese populationHiroshi Yamazaki
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194 8543, Japan
Mol Genet Metab 90:58-63. 2007..The results suggest that individuals homozygous for either of the nonsense mutations, Arg500Stop and/or Cys197Stop alleles, in the FMO3 gene can possess abnormal TMA N-oxygenation... - Mild trimethylaminuria observed in a Japanese cohort with liver damageHiroshi Yamazaki
Am J Med 118:803-5. 2005 - Genetic and environmental influences on therapeutic and toxicity outcomes: studies with CYP2A6Soisungwan Satarug
National Research Centre for Environmental Toxicology, The University of Queensland, Brisbane, Queensland, Australia
Curr Clin Pharmacol 1:291-309. 2006..The results indicate that the phenotype of CYP2A6 enzyme in liver is an outcome of interactions between the CYP2A6 gene, cadmium, nicotine and possibly its metabolites... - Curcuminoids inhibit multiple human cytochromes P450, UDP-glucuronosyltransferase, and sulfotransferase enzymes, whereas piperine is a relatively selective CYP3A4 inhibitorLaurie P Volak
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111, USA
Drug Metab Dispos 36:1594-605. 2008..Based on these data and expected tissue concentrations of inhibitors, we predict that a p.o. administered curcuminoid/piperine combination is most likely to inhibit CYP3A, CYP2C9, UGT, and SULT metabolism within the intestinal mucosa...
Research Grants
- Biosensor for real-time chemical monitoringJohn Cashman; Fiscal Year: 2007..The final sensitive and selective product will be of use in a rapid screening format of physiological fluids for OP exposure. ..
- New Opioids for AlcoholismJohn Cashman; Fiscal Year: 2006..The potential commercial application of the work is that the research could lead to a 'blockbuster' drug product. ..
- Amine N-Oxygenation by FMO3 and FMO4John Cashman; Fiscal Year: 2005..Such fundamental information will be useful in the development of safer drugs, the prevention of adverse drug reactions and the protection of humans from disease. ..
- COMBINATORIAL PHARMACOTHERAPIES FOR COCAINE DEPENDENCEJohn Cashman; Fiscal Year: 2001..The study will provide an understanding of the structural and pharmaceutical properties of hDAT antagonists. The work will lead to new insight into the preparation of human medications necessary in the cessation of cocaine abuse. ..