Brown J

References (8)

Title : From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease - Brown_2021_Cell_184_5886
Author(s) : Brown AJH , Bradley SJ , Marshall FH , Brown GA , Bennett KA , Brown J , Cansfield JE , Cross DM , de Graaf C , Hudson BD , Dwomoh L , Dias JM , Errey JC , Hurrell E , Liptrot J , Mattedi G , Molloy C , Nathan PJ , Okrasa K , Osborne G , Patel JC , Pickworth M , Robertson N , Shahabi S , Bundgaard C , Phillips K , Broad LM , Goonawardena AV , Morairty SR , Browning M , Perini F , Dawson GR , Deakin JFW , Smith RT , Sexton PM , Warneck J , Vinson M , Tasker T , Tehan BG , Teobald B , Christopoulos A , Langmead CJ , Jazayeri A , Cooke RM , Rucktooa P , Congreve MS , Weir M , Tobin AB
Ref : Cell , 184 :5886 , 2021
Abstract : Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.
ESTHER : Brown_2021_Cell_184_5886
PubMedSearch : Brown_2021_Cell_184_5886
PubMedID: 34822784

Title : The zebrafish reference genome sequence and its relationship to the human genome - Howe_2013_Nature_496_498
Author(s) : Howe K , Clark MD , Torroja CF , Torrance J , Berthelot C , Muffato M , Collins JE , Humphray S , McLaren K , Matthews L , Mclaren S , Sealy I , Caccamo M , Churcher C , Scott C , Barrett JC , Koch R , Rauch GJ , White S , Chow W , Kilian B , Quintais LT , Guerra-Assuncao JA , Zhou Y , Gu Y , Yen J , Vogel JH , Eyre T , Redmond S , Banerjee R , Chi J , Fu B , Langley E , Maguire SF , Laird GK , Lloyd D , Kenyon E , Donaldson S , Sehra H , Almeida-King J , Loveland J , Trevanion S , Jones M , Quail M , Willey D , Hunt A , Burton J , Sims S , McLay K , Plumb B , Davis J , Clee C , Oliver K , Clark R , Riddle C , Elliot D , Threadgold G , Harden G , Ware D , Begum S , Mortimore B , Kerry G , Heath P , Phillimore B , Tracey A , Corby N , Dunn M , Johnson C , Wood J , Clark S , Pelan S , Griffiths G , Smith M , Glithero R , Howden P , Barker N , Lloyd C , Stevens C , Harley J , Holt K , Panagiotidis G , Lovell J , Beasley H , Henderson C , Gordon D , Auger K , Wright D , Collins J , Raisen C , Dyer L , Leung K , Robertson L , Ambridge K , Leongamornlert D , McGuire S , Gilderthorp R , Griffiths C , Manthravadi D , Nichol S , Barker G , Whitehead S , Kay M , Brown J , Murnane C , Gray E , Humphries M , Sycamore N , Barker D , Saunders D , Wallis J , Babbage A , Hammond S , Mashreghi-Mohammadi M , Barr L , Martin S , Wray P , Ellington A , Matthews N , Ellwood M , Woodmansey R , Clark G , Cooper J , Tromans A , Grafham D , Skuce C , Pandian R , Andrews R , Harrison E , Kimberley A , Garnett J , Fosker N , Hall R , Garner P , Kelly D , Bird C , Palmer S , Gehring I , Berger A , Dooley CM , Ersan-Urun Z , Eser C , Geiger H , Geisler M , Karotki L , Kirn A , Konantz J , Konantz M , Oberlander M , Rudolph-Geiger S , Teucke M , Lanz C , Raddatz G , Osoegawa K , Zhu B , Rapp A , Widaa S , Langford C , Yang F , Schuster SC , Carter NP , Harrow J , Ning Z , Herrero J , Searle SM , Enright A , Geisler R , Plasterk RH , Lee C , Westerfield M , de Jong PJ , Zon LI , Postlethwait JH , Nusslein-Volhard C , Hubbard TJ , Roest Crollius H , Rogers J , Stemple DL
Ref : Nature , 496 :498 , 2013
Abstract : Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.
ESTHER : Howe_2013_Nature_496_498
PubMedSearch : Howe_2013_Nature_496_498
PubMedID: 23594743
Gene_locus related to this paper: danre-1neur , danre-ABHD10b , danre-a9jrf7 , danre-d2x2g3 , danre-e7ezq9 , danre-e7ff77 , danre-ndr3 , danre-nlgn4a , danre-q1mti5 , danre-q6nyz4 , danre-q6p2u2 , danre-q7t359 , danre-q08c93 , danre-A2BGU9 , danre-f1q676 , danre-e7f0z8 , danre-e7ez27 , danre-e7f2w1 , danre-f1qid7 , danre-a0a0g2kru2 , danre-f1qla7 , danre-a9jr90 , danre-e7f070 , danre-f172a , danre-e7fb35 , danre-a7mbu9 , danre-f1qtr2

Title : Potentiation of analgesic efficacy but not side effects: co-administration of an alpha4beta2 neuronal nicotinic acetylcholine receptor agonist and its positive allosteric modulator in experimental models of pain in rats - Zhu_2011_Biochem.Pharmacol_82(8)_967
Author(s) : Zhu CZ , Chin CL , Rustay NR , Zhong C , Mikusa J , Chandran P , Salyers A , Gomez E , Simler G , Lewis LG , Gauvin D , Baker S , Pai M , Tovcimak A , Brown J , Komater V , Fox GB , Decker MW , Jacobson PB , Gopalakrishnan M , Lee CH , Honore P
Ref : Biochemical Pharmacology , 82 :967 , 2011
Abstract : Positive modulation of the neuronal nicotinic acetylcholine receptor (nAChR) alpha4beta2 subtype by selective positive allosteric modulator NS-9283 has shown to potentiate the nAChR agonist ABT-594-induced anti-allodynic activity in preclinical neuropathic pain. To determine whether this benefit can be extended beyond neuropathic pain, the present study examined the analgesic activity and adverse effect profile of co-administered NS-9283 and ABT-594 in a variety of preclinical models in rats. The effect of the combined therapy on drug-induced brain activities was also determined using pharmacological magnetic resonance imaging. In carrageenan-induced thermal hyperalgesia, co-administration of NS-9283 (3.5 mumol/kg, i.p.) induced a 6-fold leftward shift of the dose-response of ABT-594 (ED(50)=26 vs. 160 nmol/kg, i.p.). In the paw skin incision model of post-operative pain, co-administration of NS-9283 similarly induced a 6-fold leftward shift of ABT-594 (ED(50)=26 vs. 153 nmol/kg). In monoiodo-acetate induced knee joint pain, co-administration of NS-9283 enhanced the potency of ABT-594 by 5-fold (ED(50)=1.0 vs. 4.6 nmol/kg). In pharmacological MRI, co-administration of NS-9283 was shown to lead to a leftward shift of ABT-594 dose-response for cortical activation. ABT-594 induced CNS-related adverse effects were not exacerbated in presence of an efficacious dose of NS-9283 (3.5 mumol/kg). Acute challenge of NS-9283 produced no cross sensitization in nicotine-conditioned animals. These results demonstrate that selective positive allosteric modulation at the alpha4beta2 nAChR potentiates nAChR agonist-induced analgesic activity across neuropathic and nociceptive preclinical pain models without potentiating ABT-594-mediated adverse effects, suggesting that selective positive modulation of alpha4beta2 nAChR by PAM may represent a novel analgesic approach.
ESTHER : Zhu_2011_Biochem.Pharmacol_82(8)_967
PubMedSearch : Zhu_2011_Biochem.Pharmacol_82(8)_967
PubMedID: 21620806

Title : Poster: In vivo characterization of the co-administration of alpha4\/beta2 neuronal nicotinic receptor agonist and positive allosteric modulator in experimental pain in rats -
Author(s) : Zhu CZ , Chin C-l , Zhong C , Mikusa J , Chandran P , Salyers A , Wensink E , Silmer G , Lewis LG , Gauvin D , Baker S , Tovcimak A , Brown J , Rustay N , Fox GB , Decker MW , Lee C-H , Gopalakrishnan M , Honore P
Ref : Biochemical Pharmacology , 78 :920 , 2009
PubMedID:

Title : Old and new pharmacology: positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor by the 5-hydroxytryptamine(2B\/C) receptor antagonist SB-206553 (3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b']di pyrrole-1(2H)-carboxamide) - Dunlop_2009_J.Pharmacol.Exp.Ther_328_766
Author(s) : Dunlop J , Lock T , Jow B , Sitzia F , Grauer S , Jow F , Kramer A , Bowlby MR , Randall A , Kowal D , Gilbert A , Comery TA , Larocque J , Soloveva V , Brown J , Roncarati R
Ref : Journal of Pharmacology & Experimental Therapeutics , 328 :766 , 2009
Abstract : The alpha7 nicotinic acetylcholine receptor (nAChR) has been implicated in Alzheimer's disease and schizophrenia, leading to efforts targeted toward discovering agonists and positive allosteric modulators (PAMs) of this receptor. In a Ca2+ flux fluorometric imaging plate reader assay, SB-206553 (3,5-dihydro-5-methyl -N-3-pyridinylbenzo [1, 2-b:4,5 -b']-di pyrrole-1(2H)-carboxamide), a compound known as a 5-hydroxytryptamine(2B/2C) receptor antagonist, produced an 8-fold potentiation of the evoked calcium signal in the presence of an EC(20) concentration of nicotine and a corresponding EC(50) of 1.5 muM for potentiation of EC(20) nicotine responses in GH4C1 cells expressing the alpha7 receptor. SB-206553 was devoid of direct alpha7 receptor agonist activity and selective against other nicotinic receptors. Confirmation of the PAM activity of SB-206553 on the alpha7 nAChR was obtained in patch-clamp electrophysiological experiments in GH4C1 cells, where it failed to evoke any detectable currents when applied alone, yet dramatically potentiated the currents evoked by an EC(20) (17 microM) and EC(100) (124 microM) of acetylcholine (ACh). Native nicotinic receptors in CA1 stratum radiatum interneurons of rat hippocampal slices could also be activated by ACh (200 microM), an effect that was entirely blocked by the alpha7-selective antagonist methyllycaconitine (MLA). These ACh currents were potentiated by SB-206553, which increased the area of the current response significantly, resulting in a 40-fold enhancement at 100 microM. In behavioral experiments in rats, SB-206553 reversed an MK-801 (dizocilpine maleate)-induced deficit in the prepulse inhibition of acoustic startle response, an effect attenuated in the presence of MLA. This latter observation provides further evidence in support of the potential therapeutic utility of alpha7 nAChR PAMs in schizophrenia.
ESTHER : Dunlop_2009_J.Pharmacol.Exp.Ther_328_766
PubMedSearch : Dunlop_2009_J.Pharmacol.Exp.Ther_328_766
PubMedID: 19050173

Title : Cloning, Characterization, Controlled Overexpression, and Inactivation of the Major Tributyrin Esterase Gene of Lactococcus lactis. -
Author(s) : Fernandez L , Beerthuyzen MM , Brown J , Siezen RJ , Coolbear T , Holland R , Kuipers OP
Ref : Applied Environmental Microbiology , 66 :1360 , 2000
PubMedID: 10742212
Gene_locus related to this paper: lacla-ESTA

Title : SCH 57790: a novel M2 receptor selective antagonist - Lachowicz_1999_Life.Sci_64(6-7)_535
Author(s) : Lachowicz JE , Lowe D , Duffy RA , Ruperto V , Taylor LA , Guzik H , Brown J , Berger JG , Tice M , McQuade R , Kozlowski J , Clader J , Strader CD , Murgolo N
Ref : Life Sciences , 64 :535 , 1999
Abstract : As a decrease in cholinergic neurons has been observed in Alzheimer's Disease (AD), therapeutic approaches to AD include inhibition of acetylcholinesterase to increase acetylcholine levels. Evidence suggests that acetylcholine release in the CNS is modulated by negative feedback via presynaptic M2 receptors, blockade of which should provide another means of increasing acetylcholine release. Structure-activity studies of [4-(phenylsulfonyl)phenyl]methylpiperazines led to the synthesis of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl]sulfinyl]-phenyl]-1-piperazin eacetonitrile. This compound, SCH 57790, binds to cloned human M2 receptors expressed in CHO cells with an affinity of 2.78 nM; the affinity at M1 receptors is 40-fold lower. SCH 57790 is an antagonist at M2 receptors expressed in CHO cells, as the compound blocks the inhibition of adenylyl cyclase activity mediated by the muscarinic agonist oxotremorine. This compound should be useful in assessing the potential of M2 receptor blockade for enhancement of cognition.
ESTHER : Lachowicz_1999_Life.Sci_64(6-7)_535
PubMedSearch : Lachowicz_1999_Life.Sci_64(6-7)_535
PubMedID: 10069520

Title : Lumenal location of the microsomal beta-glucuronidase-egasyn complex - Brown_1987_J.Cell.Biol_105_1571
Author(s) : Brown J , Novak EK , Takeuchi K , Moore K , Medda S , Swank RT
Ref : Journal of Cell Biology , 105 :1571 , 1987
Abstract : Mouse liver beta-glucuronidase is stabilized within microsomal vesicles by complexation with the accessory protein egasyn. The location of the beta-glucuronidase-egasyn complex and free egasyn within microsomal vesicles was investigated. Surprisingly, it was found that neither the complex nor free egasyn are intrinsic membrane components. Rather, both are either free within the vesicle lumen or only weakly bound to the inside of the vesicle membrane. This conclusion was derived from release studies using low concentrations of Triton X-100 or controlled sonication. Both the intact complex and free egasyn were released in parallel with lumenal proteins, not with intrinsic membrane components. Also, beta-glucuronidase was protected from digestion by proteinase K by the membrane of microsomal vesicles. The hydrophilic nature of both the complex and free egasyn was confirmed by phase separation experiments with the detergent Triton X-114. Egasyn is one of an unusual group of esterases that, despite being located within the lumen or only weakly bound to the lumenal surface of the endoplasmic reticulum, do not enter the secretory pathway.
ESTHER : Brown_1987_J.Cell.Biol_105_1571
PubMedSearch : Brown_1987_J.Cell.Biol_105_1571
PubMedID: 3667691
Gene_locus related to this paper: human-CES1