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Yr Athro John Atack
Timau a rolau for John Atack
Athro Emeritws
Ysgol y Biowyddorau
Trosolwg
Rwy'n ffarmacolegydd moleciwlaidd gyda dros 25 mlynedd o brofiad darganfod cyffuriau, yn bennaf ym maes niwrowyddoniaeth. Yn ystod y cyfnod hwn, rwyf wedi cyfrannu at y camau cynharaf o ddarganfod cyffuriau (adnabod targedau a dilysu targed) yr holl ffordd hyd at dreialon clinigol Cam 1 a Cham 2.
Rwyf wedi gweithio ar nifer o wahanol fathau o dargedau cyffuriau (ensymau, derbynyddion wedi'u cyplysu â phrotein a sianeli ïonau) sy'n cwmpasu ystod o glefydau niwroddirywiol (e.e. clefydau Alzheimer, Huntington a Parkinson) ac anhwylderau seiciatrig (anhwylder deubegynol, sgitsoffrenia, anhwylder gorbryder cyffredinol, iselder). Mae gen i ddiddordeb arbennig yn yr agweddau trosiadol o ddarganfod cyffuriau preclinical sy'n rhoi hyder y gall ymgeisydd cyffuriau penodol ymgysylltu â'r targed a chynhyrchu darlleniad swyddogaethol mewn dyn.
Fy hoff gyffur a mecanwaith gweithredu? Wel, byddai'n rhaid i hynny fod yn diazepam a'r derbynnydd GABAA ... Neu efallai mai cetamin a'r derbynnydd NMDA ydyw... Neu lithiwm a sut bynnag mae hynny'n gweithio mewn anhwylder deubegynol ... Heb sôn am donepezil, felly wna i ddim.
Cyhoeddiad
2026
- Neumann, E. et al., 2026. A PK/PD study on antihyperalgesia by an α2/3-GABAA receptor PAM in mice: Lack of tolerance liability and potential involvement of γ1-GABAA receptors. British Journal of Pharmacology 183 (10), pp.2324-2340. (10.1111/bph.70301)
- Uliana, D. L. et al., 2026. Novel positive allosteric modulators of alpha 5 subunit-containing GABAA receptors (α5-GABAARs) reverse the hyperdopaminergic state in a neurodevelopmental model of schizophrenia. Schizophrenia Research 291 , pp.27-36. (10.1016/j.schres.2026.02.010)
2025
- Baldwin, A. et al. 2025. Tetrahydropyrazolopyridinones as a novel class of potent and highly selective LIMK inhibitors. Journal of Medicinal Chemistry 68 (16), pp.17427-17456. (10.1021/acs.jmedchem.5c00974)
- Fdel, A. M. et al. 2025. Oxidative stress-responsive 1 kinase catalytic activity promotes triple negative breast cancer oncogenic potential. ACS pharmacology & translational science (10.1021/acsptsci.4c00603)
- Baldwin, A. G. et al. 2025. Discovery of MDI-114215: A potent and selective LIMK inhibitor to treat fragile X syndrome. Journal of Medicinal Chemistry 68 (1), pp.719-752. (10.1021/acs.jmedchem.4c02694)
2024
- Mitchell, S. J. et al., 2024. Neurosteroid modulation of synaptic and extrasynaptic GABAA receptors of the mouse nucleus accumbens. Biomolecules 14 (4) 460. (10.3390/biom14040460)
2022
- An, H. et al. 2022. A toolkit for the identification of NEAT1_2/paraspeckle modulators. Nucleic Acids Research 50 (20) e119. (10.1093/nar/gkac771)
- Ward, S. et al. 2022. Heteroaryl compounds useful in the treatment of cognitive disorders. WO2022/234271[Patent]
- Collins, R. et al. 2022. Comparative analysis of small-molecule limk1/2 inhibitors: chemical synthesis, biochemistry, and cellular activity. Journal of Medicinal Chemistry (10.1021/acs.jmedchem.2c00751)
- Noble, J. W. and Atack, J. R. 2022. Exploring Calbindin-IMPase fusion proteins structure and activity. Biochemistry and Biophysics Reports 30 101266. (10.1016/j.bbrep.2022.101266)
- Gendron, T. et al., 2022. Multi‐patient dose synthesis of [18F] Flumazenil via a copper‐mediated 18F‐fluorination. EJNMMI Radiopharmacy and Chemistry 7 5. (10.1186/s41181-022-00158-z)
2021
- Manzo, M. A. et al., 2021. Inhibition of a tonic inhibitory conductance in mouse hippocampal neurones by negative allosteric modulators of α5 subunit-containing γ-aminobutyric acid type A receptors: implications for treating cognitive deficits. British Journal of Anaesthesia 126 (3), pp.674-683. (10.1016/j.bja.2020.11.032)
2020
- Fenn, G. et al. 2020. Crystallization and structure of ebselen bound to cysteine 141 of human inositol monophosphatase (IMPase). Acta Crystallographica Section F: Structural Biology Communications F76 (10), pp.469-476. (10.1107/S2053230X20011310)
- Maramai, S. et al., 2020. Subtype selective y-Aminobutyric acid type A receptor (GABAAR) modulators acting at the benzodiazepine binding site: An update. Journal of Medicinal Chemistry 63 (7), pp.3425-3446. (10.1021/acs.jmedchem.9b01312)
- Koulouris, C. R. et al., 2020. Conformational flexibility within the small domain of human serine racemase. Acta Crystallographica Section F: Structural Biology Communications 76 (2), pp.65-73. (10.1107/S2053230X20001193)
- Ward, S. E. et al. 2020. Pharmacological characterisation of MDI-222, a novel AMPA receptor positive allosteric modulator with an improved safety profile. Journal of Psychopharmacology 34 (1), pp.93-102. (10.1177/0269881119872198)
2019
- Raulin, A. et al., 2019. The molecular basis for apolipoprotein E4 as the major risk factor for late-onset Alzheimer's disease. Journal of Molecular Biology 431 (12), pp.2248-2265. (10.1016/j.jmb.2019.04.019)
- Kraft, L. , Serpell, L. C. and Atack, J. R. 2019. A biophysical approach to the identification of novel ApoE chemical probes. Biomolecules 9 (2) 48. (10.3390/biom9020048)
2018
- Noble, J. W. et al., 2018. The X-ray structure of human calbindin-D28K: an improved model. Acta Crystallographica. Section D: Structural Biology 74 (10), pp.1008-1014. (10.1107/S2059798318011610)
- Duke, A. N. et al., 2018. Evidence that sedative effects of benzodiazepines involve unexpected GABAA receptor subtypes: Quantitative observation studies in rhesus monkeys. Journal of Pharmacology and Experimental Therapeutics 366 (1), pp.145-157. (10.1124/jpet.118.249250)
- Kraft, L. et al., 2018. Co-crystallization of human inositol monophosphatase with the lithium mimetic L-690,330. Acta Crystallographica. Section D: Structural Biology 74 (10), pp.973. (10.1107/S2059798318010380)
2017
- West, R. A. et al., 2017. African trypanosomiasis: Synthesis & SAR enabling novel drug discovery of ubiquinol mimics for trypanosome alternative oxidase. European Journal of Medicinal Chemistry 141 , pp.676-689. (10.1016/j.ejmech.2017.09.067)
- Khan, R. et al., 2017. Combining Sanford Arylations on Benzodiazepines with the nuisance effect. Advanced Synthesis & Catalysis 359 (18), pp.3261-3269. (10.1002/adsc.201700626)
2016
- Gaekens, T. et al., 2016. Lipophilic nalmefene prodrugs to achieve a one-month sustained release. Journal of Controlled Release 232 , pp.196. (10.1016/j.jconrel.2016.04.029)
- Hornyak, P. et al., 2016. Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2. Biochemical Journal 473 (13), pp.1869-1879. (10.1042/BCJ20160180)
2015
- Spurny, R. et al., 2015. Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the α7 nicotinic acetylcholine receptor. Proceedings of the National Academy of Sciences of the United States of America 112 (19) E2543. (10.1073/pnas.1418289112)
2014
- Atack, J. R. et al. 2014. JNJ-40255293, a novel adenosine A2A/A1 antagonist with efficacy in preclinical models of Parkinson's disease. ACS Chemical Neuroscience 5 (10), pp.1005-1019. (10.1021/cn5001606)
- Walker, S. et al., 2014. Development of an oligonucleotide-based fluorescence assay for the identification of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors. Analytical Biochemistry 454 , pp.17-22. (10.1016/j.ab.2014.03.004)
- Lavreysen, H. and Atack, J. 2014. Receptors: Functional assays. In: Stolerman, I. P. and Price, L. H. eds. Encyclopedia of Psychopharmacology. Berlin and Heidelberg: Springer(10.1007/978-3-642-27772-6_208-2)
2013
- Lavreysen, H. et al., 2013. Pharmacological characterization of JNJ-40068782, a new potent, selective, and systemically active positive allosteric modulator of the mGlu2 receptor and its radioligand [3H]JNJ-40068782. Journal of Pharmacology and Experimental Therapeutics 346 (3), pp.514-527. (10.1124/jpet.113.204990)
- Shinday, N. M. et al., 2013. Reinforcing effects Of compounds lacking intrinsic efficacy at α1 subunit-containing GABAA receptor subtypes in midazolam- but not cocaine-experienced Rhesus Monkeys. Neuropsychopharmacology 38 (6), pp.1006-1014. (10.1038/npp.2012.265)
2012
- Langlois, X. et al., 2012. Pharmacology of JNJ-37822681, a specific and fast-dissociating D2 antagonist for the treatment of schizophrenia. Journal of Pharmacology and Experimental Therapeutics 342 (1), pp.91-105. (10.1124/jpet.111.190702)
- Mirza, N. R. , Atack, J. and Wafford, K. 2012. Receptor subtypes: novel targets for novel medicines. Advances in Pharmacological Sciences 2012 529861. (10.1155/2012/529861)
2011
- Swanson, D. M. et al., 2011. The discovery and synthesis of JNJ 31020028, a small molecule antagonist of the Neuropeptide Y Y2 receptor. Bioorganic and Medicinal Chemistry Letters 21 (18), pp.5552-5556. (10.1016/j.bmcl.2011.06.136)
- Fischer, B. D. et al., 2011. Contribution of GABAA receptors containing α3 subunits to the therapeutic-related and side effects of benzodiazepine-type drugs in monkeys. Psychopharmacology 215 (2), pp.311-319. (10.1007/s00213-010-2142-y)
- Atack, J. et al. 2011. Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist. Journal of Psychopharmacology 25 (3), pp.329-344. (10.1177/0269881109354928)
- Atack, J. et al. 2011. MRK-409 (MK-0343), a GABAA receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans. Journal of Psychopharmacology 25 (3), pp.314-328. (10.1177/0269881109354927)
- Atack, J. 2011. GABAA receptor subtype-selective modulators. I. α2/α3-selective agonists as non-sedating anxiolytics. Current Topics in Medicinal Chemistry 11 (9), pp.1176-1202. (10.2174/156802611795371350)
- Atack, J. 2011. GABAA receptor subtype-selective modulators. II. α5-selective inverse agonists for cognition enhancement. Current Topics in Medicinal Chemistry 11 (9), pp.1203-1214. (10.2174/156802611795371314)
2010
- Eng, W. et al., 2010. Occupancy of human brain GABAA receptors by the novel α5 subtype-selective benzodiazepine site inverse agonist α5IA as measured using [11C]flumazenil PET imaging. Neuropharmacology 59 (7-8), pp.635-639. (10.1016/j.neuropharm.2010.07.024)
- Atack, J. R. 2010. Development of subtype-selective GABAA receptor compounds for the treatment of anxiety, sleep disorders and epilepsy. In: Monti, J. M. , Pandi-Perumal, S. R. and Mohler, H. eds. GABA and Sleep. Basel: Springer. , pp.25-72. (10.1007/978-3-0346-0226-6_2)
- Letavic, M. A. et al., 2010. Pre-clinical characterization of aryloxypyridine amides as histamine H3 receptor antagonists: Identification of candidates for clinical development. Bioorganic and Medicinal Chemistry Letters 20 (14), pp.4210-4214. (10.1016/j.bmcl.2010.05.041)
- Stocking, E. M. et al., 2010. Novel substituted pyrrolidines are high affinity histamine H3 receptor antagonists. Bioorganic and Medicinal Chemistry Letters 20 (9), pp.2755-2760. (10.1016/j.bmcl.2010.03.071)
- Dixon, C. I. et al., 2010. Cocaine effects on mouse incentive-learning and human addiction are linked to α2 subunit-containing GABAA receptors. Proceedings of the National Academy of Sciences 107 (5), pp.2289-2294. (10.1073/pnas.0910117107)
- Licata, S. C. et al., 2010. Discriminative stimulus effects of L-838,417 (7-tert-butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazine): Role of GABAA receptor subtypes. Neuropharmacology 58 (2), pp.357-364. (10.1016/j.neuropharm.2009.10.004)
- Shoblock, J. R. et al., 2010. In vitro and in vivo characterization of JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), a selective brain penetrant small molecule antagonist of the neuropeptide Y Y2 receptor. Psychopharmacology 208 (2), pp.265-277. (10.1007/s00213-009-1726-x)
- Atack, J. R. et al. 2010. Benzodiazepine binding site occupancy by the Novel GABAA receptor subtype-selective drug 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) in rats, primates, and humans. Journal of Pharmacology and Experimental Therapeutics 332 (1), pp.17-25. (10.1124/jpet.109.157909)
- Atack, J. R. 2010. Preclinical and clinical pharmacology of the GABAA receptor α5 subtype-selective inverse agonist α5IA. Pharmacology and Therapeutics 125 (1), pp.11-26. (10.1016/j.pharmthera.2009.09.001)
- Ator, N. A. et al., 2010. Reducing abuse liability of GABAA/Benzodiazepine ligands via selective partial agonist efficacy at α1 and α2/3 subtypes. Journal of Pharmacology and Experimental Therapeutics 332 (1), pp.4-16. (10.1124/jpet.109.158303)
2009
- Atack, J. R. 2009. GABAA receptor α2/α3 subtype-selective modulators as potential nonsedating anxiolytics. Current Topics in Behavioral Neuroscience 2 , pp.331-360. (10.1007/7854_2009_30)
Adrannau llyfrau
- Lavreysen, H. and Atack, J. 2014. Receptors: Functional assays. In: Stolerman, I. P. and Price, L. H. eds. Encyclopedia of Psychopharmacology. Berlin and Heidelberg: Springer(10.1007/978-3-642-27772-6_208-2)
- Atack, J. R. 2010. Development of subtype-selective GABAA receptor compounds for the treatment of anxiety, sleep disorders and epilepsy. In: Monti, J. M. , Pandi-Perumal, S. R. and Mohler, H. eds. GABA and Sleep. Basel: Springer. , pp.25-72. (10.1007/978-3-0346-0226-6_2)
Erthyglau
- Neumann, E. et al., 2026. A PK/PD study on antihyperalgesia by an α2/3-GABAA receptor PAM in mice: Lack of tolerance liability and potential involvement of γ1-GABAA receptors. British Journal of Pharmacology 183 (10), pp.2324-2340. (10.1111/bph.70301)
- Uliana, D. L. et al., 2026. Novel positive allosteric modulators of alpha 5 subunit-containing GABAA receptors (α5-GABAARs) reverse the hyperdopaminergic state in a neurodevelopmental model of schizophrenia. Schizophrenia Research 291 , pp.27-36. (10.1016/j.schres.2026.02.010)
- Baldwin, A. et al. 2025. Tetrahydropyrazolopyridinones as a novel class of potent and highly selective LIMK inhibitors. Journal of Medicinal Chemistry 68 (16), pp.17427-17456. (10.1021/acs.jmedchem.5c00974)
- Fdel, A. M. et al. 2025. Oxidative stress-responsive 1 kinase catalytic activity promotes triple negative breast cancer oncogenic potential. ACS pharmacology & translational science (10.1021/acsptsci.4c00603)
- Baldwin, A. G. et al. 2025. Discovery of MDI-114215: A potent and selective LIMK inhibitor to treat fragile X syndrome. Journal of Medicinal Chemistry 68 (1), pp.719-752. (10.1021/acs.jmedchem.4c02694)
- Mitchell, S. J. et al., 2024. Neurosteroid modulation of synaptic and extrasynaptic GABAA receptors of the mouse nucleus accumbens. Biomolecules 14 (4) 460. (10.3390/biom14040460)
- An, H. et al. 2022. A toolkit for the identification of NEAT1_2/paraspeckle modulators. Nucleic Acids Research 50 (20) e119. (10.1093/nar/gkac771)
- Collins, R. et al. 2022. Comparative analysis of small-molecule limk1/2 inhibitors: chemical synthesis, biochemistry, and cellular activity. Journal of Medicinal Chemistry (10.1021/acs.jmedchem.2c00751)
- Noble, J. W. and Atack, J. R. 2022. Exploring Calbindin-IMPase fusion proteins structure and activity. Biochemistry and Biophysics Reports 30 101266. (10.1016/j.bbrep.2022.101266)
- Gendron, T. et al., 2022. Multi‐patient dose synthesis of [18F] Flumazenil via a copper‐mediated 18F‐fluorination. EJNMMI Radiopharmacy and Chemistry 7 5. (10.1186/s41181-022-00158-z)
- Manzo, M. A. et al., 2021. Inhibition of a tonic inhibitory conductance in mouse hippocampal neurones by negative allosteric modulators of α5 subunit-containing γ-aminobutyric acid type A receptors: implications for treating cognitive deficits. British Journal of Anaesthesia 126 (3), pp.674-683. (10.1016/j.bja.2020.11.032)
- Fenn, G. et al. 2020. Crystallization and structure of ebselen bound to cysteine 141 of human inositol monophosphatase (IMPase). Acta Crystallographica Section F: Structural Biology Communications F76 (10), pp.469-476. (10.1107/S2053230X20011310)
- Maramai, S. et al., 2020. Subtype selective y-Aminobutyric acid type A receptor (GABAAR) modulators acting at the benzodiazepine binding site: An update. Journal of Medicinal Chemistry 63 (7), pp.3425-3446. (10.1021/acs.jmedchem.9b01312)
- Koulouris, C. R. et al., 2020. Conformational flexibility within the small domain of human serine racemase. Acta Crystallographica Section F: Structural Biology Communications 76 (2), pp.65-73. (10.1107/S2053230X20001193)
- Ward, S. E. et al. 2020. Pharmacological characterisation of MDI-222, a novel AMPA receptor positive allosteric modulator with an improved safety profile. Journal of Psychopharmacology 34 (1), pp.93-102. (10.1177/0269881119872198)
- Raulin, A. et al., 2019. The molecular basis for apolipoprotein E4 as the major risk factor for late-onset Alzheimer's disease. Journal of Molecular Biology 431 (12), pp.2248-2265. (10.1016/j.jmb.2019.04.019)
- Kraft, L. , Serpell, L. C. and Atack, J. R. 2019. A biophysical approach to the identification of novel ApoE chemical probes. Biomolecules 9 (2) 48. (10.3390/biom9020048)
- Noble, J. W. et al., 2018. The X-ray structure of human calbindin-D28K: an improved model. Acta Crystallographica. Section D: Structural Biology 74 (10), pp.1008-1014. (10.1107/S2059798318011610)
- Duke, A. N. et al., 2018. Evidence that sedative effects of benzodiazepines involve unexpected GABAA receptor subtypes: Quantitative observation studies in rhesus monkeys. Journal of Pharmacology and Experimental Therapeutics 366 (1), pp.145-157. (10.1124/jpet.118.249250)
- Kraft, L. et al., 2018. Co-crystallization of human inositol monophosphatase with the lithium mimetic L-690,330. Acta Crystallographica. Section D: Structural Biology 74 (10), pp.973. (10.1107/S2059798318010380)
- West, R. A. et al., 2017. African trypanosomiasis: Synthesis & SAR enabling novel drug discovery of ubiquinol mimics for trypanosome alternative oxidase. European Journal of Medicinal Chemistry 141 , pp.676-689. (10.1016/j.ejmech.2017.09.067)
- Khan, R. et al., 2017. Combining Sanford Arylations on Benzodiazepines with the nuisance effect. Advanced Synthesis & Catalysis 359 (18), pp.3261-3269. (10.1002/adsc.201700626)
- Gaekens, T. et al., 2016. Lipophilic nalmefene prodrugs to achieve a one-month sustained release. Journal of Controlled Release 232 , pp.196. (10.1016/j.jconrel.2016.04.029)
- Hornyak, P. et al., 2016. Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2. Biochemical Journal 473 (13), pp.1869-1879. (10.1042/BCJ20160180)
- Spurny, R. et al., 2015. Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the α7 nicotinic acetylcholine receptor. Proceedings of the National Academy of Sciences of the United States of America 112 (19) E2543. (10.1073/pnas.1418289112)
- Atack, J. R. et al. 2014. JNJ-40255293, a novel adenosine A2A/A1 antagonist with efficacy in preclinical models of Parkinson's disease. ACS Chemical Neuroscience 5 (10), pp.1005-1019. (10.1021/cn5001606)
- Walker, S. et al., 2014. Development of an oligonucleotide-based fluorescence assay for the identification of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors. Analytical Biochemistry 454 , pp.17-22. (10.1016/j.ab.2014.03.004)
- Lavreysen, H. et al., 2013. Pharmacological characterization of JNJ-40068782, a new potent, selective, and systemically active positive allosteric modulator of the mGlu2 receptor and its radioligand [3H]JNJ-40068782. Journal of Pharmacology and Experimental Therapeutics 346 (3), pp.514-527. (10.1124/jpet.113.204990)
- Shinday, N. M. et al., 2013. Reinforcing effects Of compounds lacking intrinsic efficacy at α1 subunit-containing GABAA receptor subtypes in midazolam- but not cocaine-experienced Rhesus Monkeys. Neuropsychopharmacology 38 (6), pp.1006-1014. (10.1038/npp.2012.265)
- Langlois, X. et al., 2012. Pharmacology of JNJ-37822681, a specific and fast-dissociating D2 antagonist for the treatment of schizophrenia. Journal of Pharmacology and Experimental Therapeutics 342 (1), pp.91-105. (10.1124/jpet.111.190702)
- Mirza, N. R. , Atack, J. and Wafford, K. 2012. Receptor subtypes: novel targets for novel medicines. Advances in Pharmacological Sciences 2012 529861. (10.1155/2012/529861)
- Swanson, D. M. et al., 2011. The discovery and synthesis of JNJ 31020028, a small molecule antagonist of the Neuropeptide Y Y2 receptor. Bioorganic and Medicinal Chemistry Letters 21 (18), pp.5552-5556. (10.1016/j.bmcl.2011.06.136)
- Fischer, B. D. et al., 2011. Contribution of GABAA receptors containing α3 subunits to the therapeutic-related and side effects of benzodiazepine-type drugs in monkeys. Psychopharmacology 215 (2), pp.311-319. (10.1007/s00213-010-2142-y)
- Atack, J. et al. 2011. Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist. Journal of Psychopharmacology 25 (3), pp.329-344. (10.1177/0269881109354928)
- Atack, J. et al. 2011. MRK-409 (MK-0343), a GABAA receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans. Journal of Psychopharmacology 25 (3), pp.314-328. (10.1177/0269881109354927)
- Atack, J. 2011. GABAA receptor subtype-selective modulators. I. α2/α3-selective agonists as non-sedating anxiolytics. Current Topics in Medicinal Chemistry 11 (9), pp.1176-1202. (10.2174/156802611795371350)
- Atack, J. 2011. GABAA receptor subtype-selective modulators. II. α5-selective inverse agonists for cognition enhancement. Current Topics in Medicinal Chemistry 11 (9), pp.1203-1214. (10.2174/156802611795371314)
- Eng, W. et al., 2010. Occupancy of human brain GABAA receptors by the novel α5 subtype-selective benzodiazepine site inverse agonist α5IA as measured using [11C]flumazenil PET imaging. Neuropharmacology 59 (7-8), pp.635-639. (10.1016/j.neuropharm.2010.07.024)
- Letavic, M. A. et al., 2010. Pre-clinical characterization of aryloxypyridine amides as histamine H3 receptor antagonists: Identification of candidates for clinical development. Bioorganic and Medicinal Chemistry Letters 20 (14), pp.4210-4214. (10.1016/j.bmcl.2010.05.041)
- Stocking, E. M. et al., 2010. Novel substituted pyrrolidines are high affinity histamine H3 receptor antagonists. Bioorganic and Medicinal Chemistry Letters 20 (9), pp.2755-2760. (10.1016/j.bmcl.2010.03.071)
- Dixon, C. I. et al., 2010. Cocaine effects on mouse incentive-learning and human addiction are linked to α2 subunit-containing GABAA receptors. Proceedings of the National Academy of Sciences 107 (5), pp.2289-2294. (10.1073/pnas.0910117107)
- Licata, S. C. et al., 2010. Discriminative stimulus effects of L-838,417 (7-tert-butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazine): Role of GABAA receptor subtypes. Neuropharmacology 58 (2), pp.357-364. (10.1016/j.neuropharm.2009.10.004)
- Shoblock, J. R. et al., 2010. In vitro and in vivo characterization of JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), a selective brain penetrant small molecule antagonist of the neuropeptide Y Y2 receptor. Psychopharmacology 208 (2), pp.265-277. (10.1007/s00213-009-1726-x)
- Atack, J. R. et al. 2010. Benzodiazepine binding site occupancy by the Novel GABAA receptor subtype-selective drug 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) in rats, primates, and humans. Journal of Pharmacology and Experimental Therapeutics 332 (1), pp.17-25. (10.1124/jpet.109.157909)
- Atack, J. R. 2010. Preclinical and clinical pharmacology of the GABAA receptor α5 subtype-selective inverse agonist α5IA. Pharmacology and Therapeutics 125 (1), pp.11-26. (10.1016/j.pharmthera.2009.09.001)
- Ator, N. A. et al., 2010. Reducing abuse liability of GABAA/Benzodiazepine ligands via selective partial agonist efficacy at α1 and α2/3 subtypes. Journal of Pharmacology and Experimental Therapeutics 332 (1), pp.4-16. (10.1124/jpet.109.158303)
- Atack, J. R. 2009. GABAA receptor α2/α3 subtype-selective modulators as potential nonsedating anxiolytics. Current Topics in Behavioral Neuroscience 2 , pp.331-360. (10.1007/7854_2009_30)
Patentau
- Ward, S. et al. 2022. Heteroaryl compounds useful in the treatment of cognitive disorders. WO2022/234271[Patent]
Ymchwil
Ar hyn o bryd rwy'n cymryd rhan mewn prosiectau sy'n nodi moleciwlau sy'n rhyngweithio ag isdeipiau penodol o'r derbynnydd GABAA neu isdeip AMPA o dderbynnydd glwtamad. Mae'r prosiectau hyn yn cynnwys timau amlddisgyblaethol o wyddonwyr gan ddefnyddio cemeg feddyginiaethol arloesol (dan arweiniad yr Athro Simon Ward) ac electroffisioleg (Athro. Martin Gosling a Jerry Lambert a Phrifysgol Sussex a Phrifysgol Dundee, yn y drefn honno) yn ogystal â nifer o gydweithwyr diwydiannol (ee, GSK ac AstraZeneca).
Rwyf hefyd yn cymryd rhan mewn nifer o brosiectau cyfnod cynnar ychwanegol sy'n astudio mecanwaith gweithredu lithiwm a rôl ApoE4 mewn clefyd Alzheimer yn ogystal â dulliau newydd o fodiwleiddio NMDA a swyddogaeth sianel ïon glwtamad kainate.
Rwy'n cael fy ngyrru gan yr awydd i ddatblygu triniaethau newydd ar gyfer yr anhwylderau niwroddirywiol a seiciatrig sy'n cael effaith ddofn ar gynifer o'n teuluoedd ac y mae angen meddygol sylweddol heb ei ddiwallu ar eu cyfer.
Ar hyn o bryd rwy'n Brif Ymchwilydd ar y gwobrau grant byw canlynol:
- MICA - Valium heb y tawelydd: modulatyddion derbynnydd GABAA Anxioselective ar gyfer trin anhwylderau pryder (Cyngor Ymchwil Meddygol £ 3M)
- modulatyddion derbynnydd alffa-GABAa ar gyfer trin nam gwybyddol sy'n gysylltiedig â chlefyd Huntington (Wellcome Trust £2M)
- Prawf o Gysyniad ar gyfer PAMs A5-GABAAR wrth drin seicosis (Ymddiriedolaeth Wellcome £500k)
- Datblygu moleciwlau bach fel strategaeth amnewid niwrosteroid ar gyfer trin seicosis ôl-enedigol ' (Wellcome Trust £500k)
- modulatyddion allosterig o dderbynyddion GABAA extrasynaptig ar gyfer trin iselder ôl-enedigol (MRC - DPFS £ 650k)
- Atalyddion racemase serine fel therapiwtig newydd ar gyfer iselder sy'n gwrthsefyll triniaeth (Cyngor Ymchwil Meddygol £18k)
- Cynllun busnes deillio ar gyfer prosiectau darganfod cyffuriau cam cynnar ar gyfer Sefydliad Darganfod Meddyginiaethau Prifysgol Caerdydd (iTPA £7.5k)
Ar hyn o bryd rwy'n Gyd-ymchwilydd ar y gwobrau grant byw canlynol:
- Atalyddion LIMK1 - Dull newydd, addasu clefydau ar gyfer trin syndrom X bregus (Cyngor Ymchwil Meddygol £2.5M)
- Trawsnewid triniaeth sgitsoffrenia: Dylunio a datblygu modulatyddion derbynnydd AMPA gyda phroffil diogelwch llawer gwell fel cyffuriau newydd ar gyfer trin y camweithrediad gwybyddol sy'n gysylltiedig â sgitsoffrenia ac anhwylderau CNS eraill (Wellcome Trust £4M)
- Datblygiad Assay a sgrinio trwybwn uchel ar gyfer adnabod moleciwlau bach newydd sydd â'r potensial i leihau'r storm cytokin cyfryngol NEAT1_2 yn COVID-19 (Llywodraeth Cymru - Sêr Cymru – COVID 19 £75k)
- MSH3: dull addasu clefyd i glefyd Huntington (LoQus23 Therapeutics Ltd £500k)
- Trawsnewid Cyfieithiad Caerdydd (Ymddiriedolaeth Wellcome £320k)
Bywgraffiad
Yn dilyn PhD mewn patholeg niwrocemegol yn yr Adran Patholeg yn Ysbyty Cyffredinol Newcastle, gweithiais am 5 mlynedd (1984-89) yn y Labordy Niwrowyddoniaeth yn y Sefydliad Cenedlaethol ar Heneiddio ar gampws y Sefydliadau Iechyd Cenedlaethol (NIH) ym Methesda, Maryland, gan astudio newidiadau cyn ac ôl-mortem ym niwrocemeg cleifion â chlefyd Alzheimer a syndrom Down.
Yn ystod fy nghyfnod yn yr NIH, dechreuais brosiect yn edrych ar ddatblygu atalyddion acetylcholinesterase ar gyfer trin clefyd Alzheimer. O'r fan honno, ymunais â Chanolfan Ymchwil Niwrowyddoniaeth Merck Sharp a Dohme yn Harlow lle gweithiais o 1989-2006 ar amrywiaeth o agweddau in vitro ac in vivo o ddarganfod cyffuriau niwrowyddoniaeth. Pan gaeodd y safle o ganlyniad anuniongyrchol i'r cyffur Blockbuster Merck, Vioxx, yn cael ei dynnu oddi ar y farchnad, ymunais â Janssen Pharmaceuticals, cangen fferyllol Johnson & Johnson, lle gweithiais o 2006 i 2012 (yn La Jolla i ddechrau ac yna, wedi'i ddenu gan y cwrw, sglodion a siocled, yn Beerse, Gwlad Belg).
Gadewais y diwydiant fferyllol i ymuno â Phrifysgol Sussex i helpu i sefydlu, gyda'r Athro Simon Ward, Canolfan Darganfod Cyffuriau Sussex a oedd, ynghyd ag ychwanegu'r Athro Martin Gosling, wedi ennill enw da am ddarganfod cyffuriau niwrowyddoniaeth a ffarmacoleg sianel ïonau yn benodol.
Yn haf 2017, dewisodd Simon a minnau symud i Gaerdydd, a ddenwyd gan ragoriaeth mecanwaith y clefyd a gwyddoniaeth glinigol ac ansawdd ac ysbryd cydweithredol yr ymchwilwyr y byddwn yn rhyngweithio â nhw. Fodd bynnag, rydym yn cynnal ein cysylltiadau â Martin sy'n parhau i fod yn gydweithredwr allweddol ac yn caniatáu inni ehangu ein diddordeb mewn ffarmacoleg sianel ïonau.
