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Jane Hanrahan

Senior Lecturer in Pharmaceutical Sciences and Associate Dean of Undergraduate Studies.

Qualifications

BSc (Hons) PhD (Warwick) MRACI Grad Dip EdStudies (Higher Ed)

Contact Details

University of Sydney
Phone: +61 2 9351 2078
Fax: +61 2 9351 4391
Email:
Room N408
Pharmacy Building A15
The University of Sydney
NSW 2006 Australia

Research Interests

Design and synthesis of conformationally restricted GABA analogues

GABA (1) is the major inhibitory neurotransmitter in the CNS. It is responsible for maintaining the balance between excitation and inhibition in the brain. Dysfunction of GABA receptors has been implicated in many disease states including schizophrenia, epilepsy and memory loss.

GABA is an extremely flexible molecule, which allows it to act at 3 subtypes of receptors (GABAA, GABAB, and GABAC). By designing analogues of GABA which are structurally restricted in different ways (Figure 1), we are able to target individual receptor subtypes. The compounds are tested on GABA receptors expressed in Xenopus laevis oocytes in collaboration with Dr Mary Collins. Current studies are investigating the design and synthesis of conformationally restrained alkyl phosphinic acids eg (2) as analogues of GABA that are selective GABAC antagonists.

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Flavonoids as modulators of GABA receptors (in collaboration with Professor Graham Johnston, Department of Pharmacology)

Flavonoids are found in many foods and drinks eg naringenin in grapefruit, resveratrol in red wine and apigenin in chamomile tea. They are also found in a number of herbal medicines eg, flavonoid glycosides in ginkgo biloba, amentoflavone in St John's Wort. Flavonoids are known to have a wide range of biological activities. We have recently and shown that some flavonoids, both synthetic eg (3) and natural, modulate the action of GABA at the GABAA receptor, possibly via the low affinity benzodiazepine binding site. This action appears to be devoid of many of the side-effects common to benzodiazepines. We have recently developed a rapid semi-synthetic method for the preparation of amentoflavone (4), a biflavonoid that is found in Ginkgo biloba and St John's Wort.

In collaboration with Dr David Hibbs, Faculty of Pharmacy, we are also investigating the charge density of flavonoids using high resolution X-ray crystallography. This information will then be used in the designing of novel compounds with enhanced activity.

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GABA release in the Thalamus

The thalamus is the brain's main sensory filter playing a major role in the regulation of consciousness, alertness, arousal, and possibly attention. It is the area where information is received and relayed to other areas of the brain, making it of particular interest in disorders such as epilepsy, memory dysfunction and schizophrenia because of the part it plays in processing information. The thalamus has been shown to be dysfunctional in the earliest stages of schizophrenia

We have recently found that the GABAC antagonist, TPMPA, increases K+-stimulated GABA release in the thalamic slices (250 microm x 1000 microm) but not in smaller thalamic slices (250 microm x 250 microm). This suggests that integrity of the neuronal circuitry is required. We are currently investigating the mechanism of this GABA mediated GABA release in the thalamus. We are currently continuing investigations in this area to determine more about the neuronal circuitry involved in these pathways.

Current Grants

  • Mary Collins (nee Chebib), Jane R. Hanrahan & Graham A. R. Johnston. Pfizer Pharmaceuticals (PIIP scheme) (2003). Design and synthesis of constrained analogs of gabapentin and pregabalin
  • Jane R Hanrahan, University of Sydney, Sesqui New Staff Support Scheme. (2003), GABAC Receptors and GABA Release in the Thalamus.
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Recent Publications

  1. M. Chebib, J.R. Hanrahan, R.J. Kumar, K.N. Mewett, G. Morriss, S. Wooller, G.A.R. Johnston, 3-Aminocyclopentyl)methylphosphinic acids: Novel GABAC receptor antagonists. Neuropharmacology (2007), 52(3), 779-787.
  2. J.R. Hanrahan, K.N. Mewett, M. Chebib, S. Matos, C. Eliopoulos, C. Crean, R.J. Kumar, P. Burden, G.A.R. Johnston, Diastereoselective synthesis of (±)-(3-aminocyclopentane)alkylphosphinic acids, conformationally restricted analogues of GABA. Organic & Biomolecular Chemistry (2006), 4(13), 2642-2649.
  3. G.A.R. Johnston, J.R. Hanrahan, M. Chebib, R.K. Duke, K.N. Mewett, Modulation of ionotropic GABA receptors by natural products of plant origin. Advances in pharmacology (San Diego, Calif.) (2006), 54 285-316.
  4. B.J. Hall, M. Chebib, J.R. Hanrahan, G.A.R. Johnston, 6-Methylflavanone, a more efficacious positive allosteric modulator of g-aminobutyric acid (GABA) action at human recombinant a2b2g2L than at a1b2g2L and a1b2 GABAA receptors expressed in Xenopus oocytes. European Journal of Pharmacology (2005), 512(2-3), 97-104.
  5. D.L. Crittenden, R.J. Kumar, J. R. Hanrahan, M. Chebib, M.J.T. Jordan, Stabilization of Zwitterions in Solution: Phosphinic and Phosphonic Acid GABA Analogues. J. Phys. Chem. 109, 8398-8409, (2005).
  6. M. Chebib, J.R. Hanrahan, K.N. Mewett, R.K. Duke, G.A.R. Johnston, Ionotropic GABA receptors as therapeutic targets for memory and sleep disorders. Ann. Rep. Med. Chem. 39, 13-23 (2005).
  7. R. D. Allan, J. R. Greenwood, T. W. Hambley, J. R. Hanrahan, D. E. Hibbs, S. Itani, H. W. Tran & P. Turner. Studies on Pyridazine Azide Cyclisation Reactions. Organic & Biomol. Chem. 2, 1782-1788 (2004).
  8. B.J. Hall, M. Chebib, J.R. Hanrahan & G.A.R. Johnston., Flumazenil-independent positive modulation of GABA action by 6-methylflavone at human recombinant α1β2γ2L and α1β2 GABAA receptors. European J. Pharmacol., 491, 1-8, (2004).
  9. J.E. Carland, A.M. Moore, J.R. Hanrahan, K.N. Mewett, R.K. Duke, G.A.R. Johnston & M. Chebib. Mutations of the 2' Proline in the M2 Domain of the Human GABAC rho1 Subunit Alter Agonist Responses. Neuropharm., 46, 770-781 (2004).
  10. J.R. Hanrahan, M. Chebib, N.L.M. Davucheron, B.J. Hall, G.A.R. Johnston, Semisynthetic preparation of amentoflavone: A negative modulator at GABA(A) receptors. Bioorg. Med. Chem. Lett., 13, 2281-2284 (2003).
  11. G.A.R. Johnston, M. Chebib, J. R. Hanrahan., Neurologically-active compounds. PCT Int. WO 2003045897.
  12. M.P. Waller, D.E. Hibbs, J. Overgaard, J.R. Hanrahan, T.W. Hambley, Flavone, Acta crystallogr E, 59: o767-o768 (2003).
  13. G.A.R. Johnston, M. Chebib, J. R. Hanrahan, K. N. Mewett., Current Drug Targets: CNS & Neurological Disorders, 2(4), GABAC receptors as drug targets. 265-273 (2003)
  14. D.E. Hibbs, J.R. Hanrahan, M. B. Hursthouse, D.W. Knight, J. Overgaard, P. Turner, R. O. Piltz & M. P. Waller, Experimental and Theoretical Charge Distribution in (Z)-N-Methyl-C-phenylnitrone. Organic & Biomol. Chem., 1, 1034-1040 (2003)
  15. J. R. Hanrahan, D. W. Knight & R. Salter, On the characteristics of reverse-Cope cyclizations of homoallylic sulfoxide nitrone adducts: a highly stereoselective route to pyrrolidine-N-oxides. Synlett , 1587-1589 (2001).
  16. Hall BJ, Hanrahan JR, Johnston GAR, Hambley TW and Hibbs DE, 6-Methylflavone. Acta Crystallographia, 2001, E57, o592-o593.
  17. J. R. Hanrahan, K. N. Mewett, M. Chebib, P. Burden and G. A. R. Johnston, An Improved, Versatile Synthesis of the GABAC Antagonists (1,2,5,6-Tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) and (Piperidin-4-yl)methylphosphinic acid (P4MPA). J. Chem. Soc., Perkin Trans I,, 2389-2392 (2001).
  18. H.M. Dodds, J.R. Hanrahan & L.P. Rivory, The inhibition of acetylcholinsterase by Irinotecan and related campthothecins: Key structural properties & experimental variables, Anti-cancer Drug Design. 16, 239-246, (2001).
  19. J. R. Hanrahan & D. W. Knight, A new strategy for the elaboration of pyrrolidine N-oxides using reverse-Cope elimination.,J. C. S. Chem. Commun., 2231-2232, (1998).
  20. J. R. Hanrahan, P. C. Taylor & W. Errington, The synthesis of 3-phosphonocyclobutyl amino acid analogues of glutamic acid via diethyl 3-oxycyclobutylphosphonate, a versatile synthetic intermediate., J.C.S. Perkin Trans. I, 493-502, (1997).
  21. J. R. Hanrahan, H. Navratilova, K. A. Shoberu, D. H. G. Crout, D. W. Hutchinson, S. M. Roberts & E. M. H. Wellington, Biosynthesis of aristeromycin: The role of (1R,2R,3S,4S)-1-hydroxymethylcyclopentane-2,3,4-triol., J.C.S. Perkin Trans. I, 3533-3536, (1994).
  22. J. R. Hanrahan & D. W. Hutchinson, Phase transfer catalysed synthesis of alicyclic tetraalkyl 1,1-bisphosphonates and trialkyl 1,1- phosphonocarboxylates., Tetrahedron Lett., 34, 3767-3768, (1993).
  23. D. H. G. Crout, J. R. Hanrahan & D. W. Hutchinson, A simple synthesis of 6-deoxy-D-(6-2H)-glucopyranose., Carbohyd. Res., 239, 305-307, (1993).
  24. J. R. Hanrahan, D. W. Hutchinson, The enzymatic synthesis of antiviral agents. J. Biotech. 23, 193-210, (1992)
  25. R. D. Allan, J. R. Hanrahan, T. W. Hambley, G. A. R. Johnston, K. N. Mewett & A. D. Mitrovic, Synthesis and activity of a potent N-methyl-D-aspartic acid agonist, trans-1-aminocyclobutane-1,3-dicarboxylic acid, and related phosphonic and carboxylic acids., J Med. Chem., 33, 2905-2915, (1990).
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Patents

Chebib M, Hanrahan JR, Johnston GAR. The University of Sydney and Polychip Pharmaceuticals (registered November, 2002). Neurologically-active compounds.

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