student profile: Mr James O'brien-brown


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Thesis work

Thesis title: Novel P2X7 Receptor Ligands

Supervisors: Louis RENDINA , Michael KASSIOU

Thesis abstract:

There is growing evidence suggesting that chronic inflammation is the underlying cause of several neurodegenerative and neuropsychiatric diseases, including Alzheimer’s disease, Parkinson’s disease, and major depressive disorder. The P2X7 receptor (P2X7R) plays an essential role in the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β) within the central nervous system (CNS). As such, inhibition of P2X7R-mediated signaling is an attractive therapeutic target. However, the clinical development of a P2X7R antagonist has remained elusive despite a persistent research effort by several major pharmaceutical organizations including AstraZeneca and Pfizer.

We have recently reported a structure-activity relationship (SAR) analysis of a series of adamantyl cyanoguanidines based on the aryl cyanoguanidine scaffold. These demonstrated potent P2X7R inhibition, with heterocyclic derivatives displaying favorable drug-like properties. One of the pyridyl analogues displayed an anti-depressant phenotype in mice exposed to the forced swim test, providing evidence of CNS activity. We have also thoroughly explored the adamantyl benzamide class of P2X7R antagonists, alternatively through the introduction of adamantane bioisosteres or with heteroaromatic isosteres of the benzene ring. Incorporation of the trifluoroadamantane polycycle reduces lipophilicity to facilitate CNS-penetration and increase the metabolic stability of the hydrophobic adamantane moiety. This thesis will describe recent progress made into exploring the common features of these discrete P2X7R antagonist classes in order to better understand the P2X7R pharmacophore. This insight will assist in the development of a CNS-permeable P2X7R antagonist combining the optimal features from each class.

Selected publications

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Journals

  • Callis, T., Reekie, T., O'Brien-Brown, J., Wong, E., Werry, E., Elias, N., Jorgensen, W., Tsanaktsidis, J., Rendina, L., Kassiou, M. (2018). The role of polycyclic frameworks in modulating P2X7 receptor function. Tetrahedron, 74(12), 1207-1219. [More Information]
  • O'Brien-Brown, J., Jackson, A., Reekie, T., Barron, M., Werry, E., Schiavini, P., McDonnell, M., Munoz, L., Wilkinson, S., Noll, B., Kassiou, M., et al (2017). Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7 receptor antagonists. European Journal of Medicinal Chemistry, 130, 433-439. [More Information]
  • Wong, E., Reekie, T., Werry, E., O'Brien-Brown, J., Bowyer, S., Kassiou, M. (2017). Pharmacological evaluation of a novel series of urea, thiourea and guanidine derivatives as P2X7 receptor antagonists. Bioorganic and Medicinal Chemistry Letters, 27(11), 2439-2442. [More Information]
  • Wilkinson, S., Barron, M., O'Brien-Brown, J., Janssen, B., Stokes, L., Werry, E., Chishty, M., Skarratt, K., Ong, J., Hibbs, D., Fuller, S., Kassiou, M., et al (2017). Pharmacological evaluation of novel bioisosteres of an adamantanyl benzamide P2X7 receptor antagonist. ACS Chemical Neuroscience, 8(11), 2374-2380. [More Information]
  • Manohar, M., Banister, S., Beinat, C., O'Brien-Brown, J., Kassiou, M. (2015). Recent advances in the development of sigma-1 receptor ligands. Australian Journal of Chemistry, 68, 600-609. [More Information]
  • Beinat, C., Reekie, T., Banister, S., O'Brien-Brown, J., Xie, T., Olson, T., Xiao, Y., Harvey, A., O'Connor, S., Coles, C., Kassiou, M., et al (2015). Structure-activity relationship studies of SEN12333 analogues: Determination of the optimal requirements for binding affinities at alpha7 nAChRs through incorporation of known structural motifs. European Journal of Medicinal Chemistry, 95, 277-301. [More Information]

2018

  • Callis, T., Reekie, T., O'Brien-Brown, J., Wong, E., Werry, E., Elias, N., Jorgensen, W., Tsanaktsidis, J., Rendina, L., Kassiou, M. (2018). The role of polycyclic frameworks in modulating P2X7 receptor function. Tetrahedron, 74(12), 1207-1219. [More Information]

2017

  • O'Brien-Brown, J., Jackson, A., Reekie, T., Barron, M., Werry, E., Schiavini, P., McDonnell, M., Munoz, L., Wilkinson, S., Noll, B., Kassiou, M., et al (2017). Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7 receptor antagonists. European Journal of Medicinal Chemistry, 130, 433-439. [More Information]
  • Wong, E., Reekie, T., Werry, E., O'Brien-Brown, J., Bowyer, S., Kassiou, M. (2017). Pharmacological evaluation of a novel series of urea, thiourea and guanidine derivatives as P2X7 receptor antagonists. Bioorganic and Medicinal Chemistry Letters, 27(11), 2439-2442. [More Information]
  • Wilkinson, S., Barron, M., O'Brien-Brown, J., Janssen, B., Stokes, L., Werry, E., Chishty, M., Skarratt, K., Ong, J., Hibbs, D., Fuller, S., Kassiou, M., et al (2017). Pharmacological evaluation of novel bioisosteres of an adamantanyl benzamide P2X7 receptor antagonist. ACS Chemical Neuroscience, 8(11), 2374-2380. [More Information]

2015

  • Manohar, M., Banister, S., Beinat, C., O'Brien-Brown, J., Kassiou, M. (2015). Recent advances in the development of sigma-1 receptor ligands. Australian Journal of Chemistry, 68, 600-609. [More Information]
  • Beinat, C., Reekie, T., Banister, S., O'Brien-Brown, J., Xie, T., Olson, T., Xiao, Y., Harvey, A., O'Connor, S., Coles, C., Kassiou, M., et al (2015). Structure-activity relationship studies of SEN12333 analogues: Determination of the optimal requirements for binding affinities at alpha7 nAChRs through incorporation of known structural motifs. European Journal of Medicinal Chemistry, 95, 277-301. [More Information]

Note: This profile is for a student at the University of Sydney. Views presented here are not necessarily those of the University.