Patel M

References (14)

Title : Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer's disease - Adnan_2023_Front.Pharmacol_14_1276179
Author(s) : Adnan M , Dasgupta D , Anwar S , Shamsi A , Siddiqui AJ , Snoussi M , Bardakci F , Patel M , Hassan MI
Ref : Front Pharmacol , 14 :1276179 , 2023
Abstract : Introduction: Hyperphosphorylation of tau is an important event in Alzheimer's disease (AD) pathogenesis, leading to the generation of "neurofibrillary tangles," a histopathological hallmark associated with the onset of AD and related tauopathies. Microtubule-affinity regulating kinase 4 (MARK4) is an evolutionarily conserved Ser-Thr (S/T) kinase that phosphorylates tau and microtubule-associated proteins, thus playing a critical role in AD pathology. The uncontrolled neuronal migration is attributed to overexpressed MARK4, leading to disruption in microtubule dynamics. Inhibiting MARK4 is an attractive strategy in AD therapeutics. Methods: Molecular docking was performed to see the interactions between MARK4 and galantamine (GLT). Furthermore, 250 ns molecular dynamic studies were performed to investigate the stability and conformational dynamics of the MARK4-GLT complex. We performed fluorescence binding and isothermal titration calorimetry studies to measure the binding affinity between GLT and MARK4. Finally, an enzyme inhibition assay was performed to measure the MARK4 activity in the presence and absence of GLT. Results: We showed that GLT, an acetylcholinesterase inhibitor, binds to the active site cavity of MARK4 with an appreciable binding affinity. Molecular dynamic simulation for 250 ns demonstrated the stability and conformational dynamics of the MARK4-GLT complex. Fluorescence binding and isothermal titration calorimetry studies suggested a strong binding affinity. We further show that GLT inhibits the kinase activity of MARK4 significantly (IC(50) = 5.87 microM). Conclusion: These results suggest that GLT is a potential inhibitor of MARK4 and could be a promising therapeutic target for AD. GLT's inhibition of MARK4 provides newer insights into the mechanism of GLT's action, which is already used to improve cognition in AD patients.
ESTHER : Adnan_2023_Front.Pharmacol_14_1276179
PubMedSearch : Adnan_2023_Front.Pharmacol_14_1276179
PubMedID: 37795023

Title : Interplay between MYZUS PERSICAE-INDUCED LIPASE 1 and OPDA signaling in limiting green peach aphid infestation on Arabidopsis thaliana - Archer_2023_J.Exp.Bot__
Author(s) : Archer L , Mondal HA , Behera S , Twayana M , Patel M , Louis J , Nalam VJ , Keereetaweep J , Chowdhury Z , Shah J
Ref : J Exp Bot , : , 2023
Abstract : MYZUS PERSICAE-INDUCED LIPASE1 (MPL1) encodes a lipase in Arabidopsis thaliana that is required for limiting infestation by the green peach aphid (GPA; Myzus persicae), an important phloem sap-consuming insect pest. Previously, we demonstrated that MPL1 expression was upregulated in response to GPA infestation, and GPA fecundity was higher on the mpl1 mutant, compared to the wild-type (WT), and lower on 35S:MPL1 plants that constitutively expressed MPL1 from the 35S promoter. Here, we show that the MPL1 promoter is active in the phloem and expression of the MPL1 coding sequence from the phloem-specific SUC2 promoter is sufficient to restore resistance to the GPA in mpl1. The GPA infestation-associated upregulation of MPL1 requires CYCLOPHILIN 20-3 (CYP20-3), which encodes a 12-oxo-phytodienoic acid (OPDA)-binding protein that is involved in OPDA signaling and is required for limiting GPA infestation. OPDA promotes MPL1 expression to limit GPA fecundity, a process that requires CYP20-3 function. These results along with our observation that constitutive expression of MPL1 from the 35S promoter restores resistance to the GPA in the cyp20-3 mutant, and MPL1 feedbacks to limit OPDA levels in GPA-infested plants, suggest that an interplay between MPL1, OPDA, and CYP20-3 contributes to resistance to the GPA.
ESTHER : Archer_2023_J.Exp.Bot__
PubMedSearch : Archer_2023_J.Exp.Bot__
PubMedID: 37696760
Gene_locus related to this paper: arath-LIP2

Title : Cavity surface residues of PAD4 and SAG101 contribute to EDS1 dimer signaling specificity in plant immunity - Dongus_2022_Plant.J__
Author(s) : Dongus JA , Bhandari DD , Penner E , Lapin D , Stolze SC , Harzen A , Patel M , Archer L , Dijkgraaf L , Shah J , Nakagami H , Parker JE
Ref : Plant J , : , 2022
Abstract : Arabidopsis pathogen effector-triggered immunity (ETI) is controlled by a family of three lipase-like proteins EDS1, PAD4 and SAG101 and two sub-families of HET-S/LOB-B (HeLo)-domain "helper" NLRs, ADR1s and NRG1s. EDS1-PAD4 dimers cooperate with ADR1s, and EDS1-SAG101 dimers with NRG1s, in two separate defense-promoting modules. EDS1-PAD4-ADR1 and EDS1-SAG101-NRG1 complexes were detected in immune-activated leaf extracts but the molecular determinants for specific complex formation and function remain unknown. EDS1 signaling is mediated by a C-terminal EP domain (EPD) surface surrounding a cavity formed by the heterodimer. Here we investigated whether the EPDs of PAD4 and SAG101 contribute to EDS1 dimer functions. Using a structure-guided approach, we undertook a comprehensive mutational analysis of Arabidopsis PAD4. We identify two conserved residues (Arg314 and Lys380) lining the PAD4 EPD cavity that are essential for EDS1-PAD4 mediated pathogen resistance, but are dispensible for PAD4 mediated restriction of green peach aphid infestation. Positionally equivalent Met304 and Arg373 at the SAG101 EPD cavity are required for EDS1-SAG101 promotion of ETI-related cell death. In a PAD4 and SAG101 interactome analysis of ETI-activated tissues, PAD4(R314A) and SAG101(M304R) EPD variants maintain interaction with EDS1 but lose association, respectively, with helper NLRs ADR1-L1 and NRG1.1, and other immune-related proteins. Our data reveal a fundamental contribution of similar but non-identical PAD4 and SAG101 EPD surfaces to specific EDS1 dimer protein interactions and pathogen immunity.
ESTHER : Dongus_2022_Plant.J__
PubMedSearch : Dongus_2022_Plant.J__
PubMedID: 35324052
Gene_locus related to this paper: arath-At5g14930 , arath-eds1 , arath-PAD4

Title : 3D-Printed Enzyme-Embedded Plastics - Greene_2021_Biomacromolecules_22_1999
Author(s) : Greene AF , Vaidya A , Collet C , Wade KR , Patel M , Gaugler M , West M , Petcu M , Parker K
Ref : Biomacromolecules , 22 :1999 , 2021
Abstract : A simple and environmentally friendly approach toward the thermoplastic processing of rapidly degradable plastic-enzyme composites using three-dimensional (3D) printing techniques is described. Polycaprolactone/Amano lipase (PCL/AL) composite films (10 mm x 10 mm; height [h] = -400 microm) with an AL loading of 0.1, 1.0, and 5.0% were prepared via 3D printing techniques that entail direct mixing in the solid state and thermal layer-by-layer extrusion. It was found that AL can tolerate in situ processing temperatures up to 130 degreesC in the solid-state for 60 min without loss of enzymatic activity. The composites were degraded in phosphate buffer (8 mg/mL, composite to buffer) for 7 days at 37 degreesC and the resulting average percent total weight loss (WL(avg %)) was found to be 5.2, 92.9, and 100%, for the 0.1, 1.0, and 5.0% films, respectively. The degradation rates of PCL/AL composites were found to be faster than AL applied externally in the buffer. Thicker PCL/AL 1.0% films (10 mm x 10 mm; h = -500 microm) were also degraded over a 7 day period to examine how the weight loss occurs over time with 3.0, 18.1, 36.4, 46.4, and 70.2% weight loss for days 1, 2, 3, 4, and 7, respectively. Differential scanning calorimetry (DSC) analysis shows that the film's percent crystallinity (D(xtal%)) increases over time with D(xtal%) = 46.5 for day 0 and 53.1% for day 7. Scanning electron microscopy (SEM) analysis found that film erosion begins at the surface and that water can penetrate the interior via surface pores activating the enzymes embedded in the film. Controlled release experiments utilizing dye-loaded PCL/AL/dye (AL = 1.0%; dye = 0.1%) composites were degraded over a 7 day period with the bulk of the dye released by the fourth day. The PCL/AL multimaterial objects containing AL-resistant polylactic acid (PLA) were also printed and degraded to demonstrate the application of this material on more complex structures.
ESTHER : Greene_2021_Biomacromolecules_22_1999
PubMedSearch : Greene_2021_Biomacromolecules_22_1999
PubMedID: 33870685

Title : Antioxidant drug therapy as a neuroprotective countermeasure of nerve agent toxicity - Pearson-Smith_2020_Neurobiol.Dis_133_104457
Author(s) : Pearson-Smith JN , Patel M
Ref : Neurobiol Dis , 133 :104457 , 2020
Abstract : The use of chemical warfare agents is an ongoing, significant threat to both civilians and military personnel worldwide. Nerve agents are by far the most formidable toxicants in terms of their lethality and toxicity. Nerve agents initiate neurotoxicity by the irreversible inhibition of acetylcholinesterase and resultant accumulation of acetylcholine in excitable tissues. The cholinergic toxidrome presents as miosis, lacrimation, diarrhea, fasciculations, seizures, respiratory arrest and coma. Current medical countermeasures can attenuate acute mortality and confer limited protection against secondary neuronal injury when given rapidly after exposure. However, there is an urgent need for the development of novel, add-on neuroprotective therapies to prevent mortality and long-term toxicity of nerve agents. Increasing evidence suggests that pathways other than direct acetylcholinesterase inhibition contribute to neurotoxicity and secondary neuronal injury. Among these, oxidative stress is emerging as a key therapeutic target for nerve agent toxicity. In this review, we discuss the rationale for targeting oxidative stress in nerve agent toxicity and highlight research investigating antioxidant therapy as a neuroprotective medical countermeasure to attenuate oxidative stress, neuroinflammation and neurodegeneration.
ESTHER : Pearson-Smith_2020_Neurobiol.Dis_133_104457
PubMedSearch : Pearson-Smith_2020_Neurobiol.Dis_133_104457
PubMedID: 31028872

Title : Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity - Mahy_2020_J.Med.Chem_63_9464
Author(s) : Mahy W , Patel M , Steadman D , Woodward HL , Atkinson BN , Svensson F , Willis NJ , Flint A , Papatheodorou D , Zhao Y , Vecchia L , Ruza RR , Hillier J , Frew S , Monaghan A , Costa A , Bictash M , Walter MW , Jones EY , Fish PV
Ref : Journal of Medicinal Chemistry , 63 :9464 , 2020
Abstract : The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole 20, guided by structure-based drug design, identified 20z as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine 8 gave acid 26. This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable in vitro ADME profiles.
ESTHER : Mahy_2020_J.Med.Chem_63_9464
PubMedSearch : Mahy_2020_J.Med.Chem_63_9464
PubMedID: 32787107
Gene_locus related to this paper: human-NOTUM

Title : Rivastigmine does not alter cocaine-induced subjective effects or self-administration - Patel_2019_Pharmacol.Biochem.Behav__172758
Author(s) : Patel M , Verrico CD , De La Garza R, 2nd
Ref : Pharmacol Biochem Behav , :172758 , 2019
Abstract : BACKGROUND: Acetylcholinergic (ACh) neurons interface with the mesolimbic dopamine pathway implicated in addiction, and acetylcholinesterase inhibitors (AChEis) have been shown to reduce the immediate effects of cocaine and amount used. Our study is the first to examine if the safe and low-interaction AChEi rivastigmine (riv) alters the subjective effects produced by cocaine administration. METHODS: Cocaine-dependent subjects were randomized to daily placebo, riv 3mg, or riv 6mg, administered inpatient for 10days. On day 1 (pre-dose) and day 9, subjects received both IV cocaine 40mg or placebo in a randomized order with subsequent serial assessments of visual analog scale (VAS) subjective effects and pharmacokinetic measurements. On day 10 all participants received one baseline dose of cocaine 20mg with assessment of subjective effects, and were then able to purchase additional doses at 15min intervals with study earnings. RESULTS: 40 subjects were randomized to placebo (n=16), riv 3mg (n=13), or riv 6mg (n=12). All subjects completed the study and there were no demographic differences between treatment groups. Pre- and post- treatment, there were no significant pharmacokinetic differences (blood levels of cocaine, BE, EME) following cocaine administration. In a two-way ANOVA, IV cocaine significantly increased positive VAS category ratings compared to placebo, but rivastigmine treatment at either dose had no significant effect on any VAS category ratings. Similarly, there was no significant rivastigmine effect on any category in the day 10 cocaine administration, and no effect on number of subsequent doses participants purchased. CONCLUSION: Rivastigmine 3 or 6mg had no significant effect on the subjective effects of cocaine after 9days of treatment. This is an important finding as other drugs in the AChEi class (donepezil, Huperzine A) have produced significant results, but differ in their receptor specificity and PK parameters.
ESTHER : Patel_2019_Pharmacol.Biochem.Behav__172758
PubMedSearch : Patel_2019_Pharmacol.Biochem.Behav__172758
PubMedID: 31430484

Title : Neuroprotective effects of a catalytic antioxidant in a rat nerve agent model - Liang_2018_Redox.Biol_20_275
Author(s) : Liang LP , Pearson-Smith JN , Huang J , Day BJ , Patel M
Ref : Redox Biol , 20 :275 , 2018
Abstract : Persistent inhibition of acetylcholinesterase resulting from exposure to nerve agents such as soman, is associated with prolonged seizure activity known as status epilepticus (SE). Without medical countermeasures, exposure to soman and resultant SE leads to high morbidity and mortality. Currently available therapeutics are effective in limiting mortality, however effects on morbidity are highly time-dependent and rely on the ability to suppress SE. We have previously demonstrated significant protection from secondary neuronal injury in surrogate nerve agent models by targeting oxidative stress. However, whether oxidative stress represents a relevant therapeutic target in genuine nerve agent toxicity is unknown. Here, we demonstrate that soman exposure results in robust region- and time-dependent oxidative stress. Targeting this oxidative stress in a post-exposure paradigm using a small molecular weight, broad spectrum catalytic antioxidant, was sufficient to attenuate brain and plasma oxidative stress, neuroinflammation and neurodegeneration. Thus, targeting of oxidative stress in a post-exposure paradigm can mitigate secondary neuronal injury following soman exposure.
ESTHER : Liang_2018_Redox.Biol_20_275
PubMedSearch : Liang_2018_Redox.Biol_20_275
PubMedID: 30384261

Title : The role of oxidative stress in organophosphate and nerve agent toxicity - Pearson_2016_Ann.N.Y.Acad.Sci_1378_17
Author(s) : Pearson JN , Patel M
Ref : Annals of the New York Academy of Sciences , 1378 :17 , 2016
Abstract : Organophosphate (OP) nerve agents exert their toxicity through inhibition of acetylcholinesterase. The excessive stimulation of cholinergic receptors rapidly causes neuronal damage, seizures, death, and long-term neurological impairment in those that survive. Owing to the lethality of organophosphorus agents and the growing risk they pose, medical interventions that prevent OP toxicity and the delayed injury response are much needed. Studies have shown that oxidative stress occurs in models of subacute, acute, and chronic exposure to OP agents. Key findings of these studies include alterations in mitochondrial function and increased free radical-mediated injury, such as lipid peroxidation. This review focuses on the role of reactive oxygen species in OP neurotoxicity and its dependence on seizure activity. Understanding the sources, mechanisms, and pathological consequences of OP-induced oxidative stress can lead to the development of rational therapies for treating toxic exposures.
ESTHER : Pearson_2016_Ann.N.Y.Acad.Sci_1378_17
PubMedSearch : Pearson_2016_Ann.N.Y.Acad.Sci_1378_17
PubMedID: 27371936

Title : EPHX1 gene polymorphisms in alcohol dependence and their distribution among the Indian populations - Bhaskar_2013_Am.J.Drug.Alcohol.Abuse_39_16
Author(s) : Bhaskar LV , Thangaraj K , Patel M , Shah AM , Gopal K , Saikrishna L , Tamang R , Singh L , Rao VR
Ref : Am J Drug Alcohol Abuse , 39 :16 , 2013
Abstract : BACKGROUND: The microsomal epoxide hydrolase is a phase II enzyme of the biotransformation. The human epoxide hydrolase 1 (EPHX1) gene lies in the chromosomal region 1q42.1 and exhibits polymorphism. Two single nucleotide polymorphisms (SNPs) have been described in the coding region of the EPHX1 gene that produces two protein variants. SUBJECTS AND
METHODS: A total of 604 samples belonging to 13 Indian populations were included in this study. Based on the DSM-IV criteria, 184 individuals from Kota population were classified into alcoholism cases (100) and controls (84). Genotypes of Tyr113His and His139Arg polymorphisms in the EPHX1 gene were determined using PCR and sequencing. Associations were tested using Pearson's chi(2) test and haplotype analyses.
RESULTS: We found significant association between EPHX1 gene Tyr113His polymorphism and alcoholism in the Kota population (T vs. C: OR = .615, 95% CI = .399-.949, p = .027; TT vs. CC + CT: OR = .536, 95% CI = .297-.969, p = .038). The very slow activity haplotype CA (113His-139His) was also found to be associated with alcohol dependence (p = .048). Analysis of additional populations demonstrated that the Tyr113His polymorphism significantly deviated from Hardy-Weinberg equilibrium in four populations but only one population deviated for the His139Arg locus. All populations shared the four possible two-site haplotypes. Linkage disequilibrium between these two loci was not significant in any of the population studied. CONCLUSION: EPHX1 gene polymorphisms and haplotypes are associated with an increased risk for alcoholism in the Kota population. This is the first report from India that will serve as a template for future investigations of the prevalence of EPHX1 alleles in association with various clinical entities.
ESTHER : Bhaskar_2013_Am.J.Drug.Alcohol.Abuse_39_16
PubMedSearch : Bhaskar_2013_Am.J.Drug.Alcohol.Abuse_39_16
PubMedID: 22257321

Title : Genomic comparison of Escherichia coli O104:H4 isolates from 2009 and 2011 reveals plasmid, and prophage heterogeneity, including shiga toxin encoding phage stx2 - Ahmed_2012_PLoS.One_7_e48228
Author(s) : Ahmed SA , Awosika J , Baldwin C , Bishop-Lilly KA , Biswas B , Broomall S , Chain PS , Chertkov O , Chokoshvili O , Coyne S , Davenport K , Detter JC , Dorman W , Erkkila TH , Folster JP , Frey KG , George M , Gleasner C , Henry M , Hill KK , Hubbard K , Insalaco J , Johnson S , Kitzmiller A , Krepps M , Lo CC , Luu T , McNew LA , Minogue T , Munk CA , Osborne B , Patel M , Reitenga KG , Rosenzweig CN , Shea A , Shen X , Strockbine N , Tarr C , Teshima H , van Gieson E , Verratti K , Wolcott M , Xie G , Sozhamannan S , Gibbons HS
Ref : PLoS ONE , 7 :e48228 , 2012
Abstract : In May of 2011, an enteroaggregative Escherichia coli O104:H4 strain that had acquired a Shiga toxin 2-converting phage caused a large outbreak of bloody diarrhea in Europe which was notable for its high prevalence of hemolytic uremic syndrome cases. Several studies have described the genomic inventory and phylogenies of strains associated with the outbreak and a collection of historical E. coli O104:H4 isolates using draft genome assemblies. We present the complete, closed genome sequences of an isolate from the 2011 outbreak (2011C-3493) and two isolates from cases of bloody diarrhea that occurred in the Republic of Georgia in 2009 (2009EL-2050 and 2009EL-2071). Comparative genome analysis indicates that, while the Georgian strains are the nearest neighbors to the 2011 outbreak isolates sequenced to date, structural and nucleotide-level differences are evident in the Stx2 phage genomes, the mer/tet antibiotic resistance island, and in the prophage and plasmid profiles of the strains, including a previously undescribed plasmid with homology to the pMT virulence plasmid of Yersinia pestis. In addition, multiphenotype analysis showed that 2009EL-2071 possessed higher resistance to polymyxin and membrane-disrupting agents. Finally, we show evidence by electron microscopy of the presence of a common phage morphotype among the European and Georgian strains and a second phage morphotype among the Georgian strains. The presence of at least two stx2 phage genotypes in host genetic backgrounds that may derive from a recent common ancestor of the 2011 outbreak isolates indicates that the emergence of stx2 phage-containing E. coli O104:H4 strains probably occurred more than once, or that the current outbreak isolates may be the result of a recent transfer of a new stx2 phage element into a pre-existing stx2-positive genetic background.
ESTHER : Ahmed_2012_PLoS.One_7_e48228
PubMedSearch : Ahmed_2012_PLoS.One_7_e48228
PubMedID: 23133618
Gene_locus related to this paper: ecoli-MCMK , ecoli-ycfp , ecoli-yqia , ecoli-YfhR

Title : Complete Genome Sequence of a thermotolerant sporogenic lactic acid bacterium, Bacillus coagulans strain 36D1 - Rhee_2011_Stand.Genomic.Sci_5_331
Author(s) : Rhee MS , Moritz BE , Xie G , Glavina Del Rio T , Dalin E , Tice H , Bruce D , Goodwin L , Chertkov O , Brettin T , Han C , Detter C , Pitluck S , Land ML , Patel M , Ou M , Harbrucker R , Ingram LO , Shanmugam KT
Ref : Stand Genomic Sci , 5 :331 , 2011
Abstract : Bacillus coagulans is a ubiquitous soil bacterium that grows at 50-55 degrees C and pH 5.0 and ferments various sugars that constitute plant biomass to L (+)-lactic acid. The ability of this sporogenic lactic acid bacterium to grow at 50-55 degrees C and pH 5.0 makes this organism an attractive microbial biocatalyst for production of optically pure lactic acid at industrial scale not only from glucose derived from cellulose but also from xylose, a major constituent of hemicellulose. This bacterium is also considered as a potential probiotic. Complete genome sequence of a representative strain, B. coagulans strain 36D1, is presented and discussed.
ESTHER : Rhee_2011_Stand.Genomic.Sci_5_331
PubMedSearch : Rhee_2011_Stand.Genomic.Sci_5_331
PubMedID: 22675583
Gene_locus related to this paper: bacco-c1p801 , bacco-g2tqg6

Title : Fatty acid amide hydrolase inhibitors display broad selectivity and inhibit multiple carboxylesterases as off-targets - Zhang_2007_Neuropharmacol_52_1095
Author(s) : Zhang D , Saraf A , Kolasa T , Bhatia P , Zheng GZ , Patel M , Lannoye GS , Richardson P , Stewart A , Rogers JC , Brioni JD , Surowy CS
Ref : Neuropharmacology , 52 :1095 , 2007
Abstract : Fatty acid amide hydrolase (FAAH) is the primary regulator of several bioactive lipid amides including anandamide. Inhibitors of FAAH are potentially useful for the treatment of pain, anxiety, depression, and other nervous system disorders. However, FAAH inhibitors must display selectivity for this enzyme relative to the numerous other serine hydrolases present in the human proteome in order to be therapeutically acceptable. Here we employed activity-based protein profiling (ABPP) to assess the selectivity of FAAH inhibitors in multiple rat and human tissues. We discovered that some inhibitors, including carbamate compounds SA-47 and SA-72, and AM404 are exceptionally selective while others, like URB597, BMS-1, OL-135, and LY2077855 are less selective, displaying multiple off-targets. Since proteins around 60kDa constitute the major off-targets for URB597 and several other FAAH inhibitors with different chemical structures, we employed the multi-dimensional protein identification technology (MudPIT) approach to analyze their identities. We identified multiple carboxylesterase isozymes as bona fide off-targets of FAAH inhibitors. Consistently, enzymatic assay confirmed inhibition of carboxylesterase activities in rat liver by FAAH inhibitors. Since carboxylesterases hydrolyze a variety of ester-containing drugs and prodrugs, we speculate that certain FAAH inhibitors, by inhibiting carboxylesterases, might have drug-drug interactions with other medicines if developed as therapeutic agents.
ESTHER : Zhang_2007_Neuropharmacol_52_1095
PubMedSearch : Zhang_2007_Neuropharmacol_52_1095
PubMedID: 17217969

Title : Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction - Cowart_2004_J.Med.Chem_47_3853
Author(s) : Cowart M , Latshaw SP , Bhatia P , Daanen JF , Rohde J , Nelson SL , Patel M , Kolasa T , Nakane M , Uchic ME , Miller LN , Terranova MA , Chang R , Donnelly-Roberts D , Namovic MT , Hollingsworth PR , Martino BR , Lynch JJ, 3rd , Sullivan JP , Hsieh GC , Moreland RB , Brioni JD , Stewart AO
Ref : Journal of Medicinal Chemistry , 47 :3853 , 2004
Abstract : A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 micromol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D4 selective agonism in this series of analogues.
ESTHER : Cowart_2004_J.Med.Chem_47_3853
PubMedSearch : Cowart_2004_J.Med.Chem_47_3853
PubMedID: 15239663