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Mary Collins (Chebib)

Associate Professor in Pharmaceutical Chemistry

Qualifications

BSc (Hon), PhD, FRACI

Contact Details

University of Sydney
Phone: +61 2 9351 8584
Fax: +61 2 9351 4391
Email:
Room 403
Badham Building A16
The University of Sydney
NSW 2006 Australia

Research Interests

  • GABA receptors
  • Nicotinic acetylcholine receptors
  • Structure-function studies

The rapid advances in molecular biology and genetics have contributed towards the discovery and isolation of a large number of receptors and proteins that may be targets to treat various disease states. Thus, it is vital that we increase the diversity of agents with which to investigate such receptors and proteins. Structure-activity relationship (SAR) studies involving structural variations of both the ligands and their receptor targets (termed complementary structure-activity studies) play important roles in drug design and development. SAR studies of ligands, and in particular conformationally restricted ligands, help us to identify the stereochemical and structural features important for activity and to determine the physiological role of receptors. Complementing these studies, structure-function studies of the proteins using mutagenesis methods help identify amino acids that are important in the binding and function of receptors when activated by these ligands. Such studies are vital to the discovery of drugs that interact selectively with particular receptor subtypes and in receptors that may have inheritable mutations.

I have developed a vigorous research program at the University of Sydney in the areas of medicinal chemistry and molecular pharmacology focusing on various ion channels, which are key targets for drugs that have important therapeutic actions on disorders such as myopia, epilepsy, anxiety, depression and memory-related deficits implicated in Alzheimer's disease and schizophrenia. With my collaborators, Graham Johnston and Jane Hanrahan, we were the first to show that TPMPA, a selective GABAC receptor antagonist enhanced memory in animal models. The problem with TPMPA is that it does not cross the blood-brain barrier and recently we developed novel and selective GABAC receptor antagonists that cross the blood-brain barrier. These agents show promising results in animal models of memory and are being evaluated in pre-clinical trials. An added bonus to the use of these agents is their ability to inhibit myopia progression in the chick model. This result was shown by our collaborator, A/Prof Katrina Schmid (School of Optometry, QUT). A total of three international patents have been granted for the development of GABAC ligands. Their extensive knowledge in the pharmacology of GABAC receptors led us to develop the most comprehensive model of the ligand-binding site. To complement these studies, we were the first to identify the 2' position of the GABAC receptor pore to be responsible for (a) changing the pharmacology of ligands from agonists to antagonists and (b) inverting the conductance of the channel from an anion to a cation conducting receptor in only one mutation. This work is important for understanding how genetic mutations associated with diseases behave towards different drug treatments.
A recent significant achievement was the synthesis and evaluation of analogues of the norditerpenoid alkaloid methyllycaconitine (MLA) as subtype selective ligands at the nicotinic acetylcholine receptor. Malcolm McLeod and I made use of a new Mannich based synthesis of the MLA piperidine ring, resulting in the first small molecule analogue of MLA that acted as a competitive antagonist at the (7 receptor subtype. A number of analogues were also found to be non-competitive antagonists at nicotinic receptors. We are now using the scanning cysteine accessibility method (SCAM) along with cysteine reactive antagonists to identify the binding site for these ligands.

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Track Record

Grant Income: I have received more than $2.5M in competitive grants from the ARC and NHMRC, more than $1.2M in industry-funded projects, including from Pfizer, Polychip Pharmaceuticals and Metabolic Pharmaceuticals.

Publications and Conferences: Since obtaining my PhD in 1994, I have published 47 fully refereed publications in medium-high impact journals including J Med Chem [IF = 5.115], J Biol Chem [IF = 5.808], Org Lett [IF = 4.659], Neuropharmacol [IF = 3.86], J Neurochem [IF = 4.26], Tox Appl Pharmacol [IF = 4.722], Br J Pharmacol [IF = 3.825], Neurosci [IF = 3.427] J Phys Chem A [IF = 3.047] and Mol Pharmacol [IF = 4.469]. The Web of Science Citation Index listed 435 non-self citations for 47-refereed manuscripts. Two publications have over a hundred citations. I have been invited to present my findings internationally at the World Chemistry Congress, Brisbane (2001) and nationally at a number of symposia including Receptors/Channels/Transporters symposium at ASCEPT (2003) and GABA and glycine receptors at Australian Neuroscience Society (1999).

Awards: I received prestigious awards including entry to Fellow of the Royal Australian Chemical Institute Inc (RACI) (2006), the ASCEPT Johnson & Johnson New Investigator Award (1998) and the RACI's BIOTA Holdings Award (2000).
Supervision and mentoring: Currently, I oversee a team consisting of 2 post-doctoral fellows and 8 PhD students. Over the last 10 years, she completed 9 PhD students both as primary and associate supervisor, and 25 honours students - 4 received university medallist and 16 received first class honours. Recently, I received the Faculty of Pharmacy Higher Degree Supervision Award.

Society membership and participation: She is a member of a number of societies including the RACI, ASCEPT, ANS and Society for Neuroscience (SfN). She has taken an active role in ASCEPT, organising the National meeting in 1999 for over 400 delegates. I served as Chair of the Biomolecular Chemistry Division (2003-2006) for the RACI. In this role, I successfully organised two major national RACI conferences: CONNECT 05 (over 1200 delegates) and Drug Design Amongst the Vines 2006 (150 delegates), and introduced the Bionomics Best Thesis Award in Medicinal Chemistry. Recently I became President of the RACI NSW Branch (2007-present).

Reviewing and refereeing: I review manuscripts for a number of international journals including J Physiol, J Clin Exp Pharmacol Physiol, Neurosci Res, Bioorg Med Chem and J Med Chem. I review applications for the ARC, NH&MRC and Diabetes Australia and have served on the NH&MRC grant review panel in 2005 and 2007.

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Research Personnel

Gracia Quek (PhD Candidate)
Navnath Gavande (PhD Candidate)
Hye-lim Kim (PhD Candidate)
Heba Abdel Halim (PhD Candidate)
Tin Thing Yow (PhD Candidate)
Jill Halliday (PhD Candidate at the School of Chemistry with Dr Mal McLeod)
Abeer Abdelhalim (PhD Candidate with Dr Jane Hanrahan)
Clarrissa Ng (PhD Candidate with Dr Jane Hanrahan)

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Scientific Collaborations

Dr Jane Hanrahan (Faculty of Pharmacy, University of Sydney)
Prof Graham AR Johnston (Adrien Albert Laboratory of Medicinal Chemistry (Department of Pharmacology, University of Sydney)
Dr Kenneth Mewett (Adrien Albert Laboratory of Medicinal Chemistry (Department of Pharmacology, University of Sydney)
Dr Sebastian Fernandez (Adrien Albert Laboratory of Medicinal Chemistry (Department of Pharmacology, University of Sydney)
Dr Meredith Jordan (School of Chemistry, University of Sydney)
Prof David Pepperberg (Chicago, USA)
Dr Malcolm McLeod (Australian National University)
Prof David Small (University of Tasmania)
A/Prof Katrina Schmid (School of Optometry, Queensland University of Technology)

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Professional Associations

Member of the Royal Australian Chemical Institute (MRACI)
Member of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT)
Neuroscience Institute of Schizophrenia and Allied Disorders (NISAD)-Affiliated Scientist
Member of the Australian Neuroscience Society (ANS)
Member of the Australian Society for Medical Research (ASMR)
Member of the Society for Neuroscience (SfN)

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Current Grants

  1. 1. Johnston GAR, Hanrahan JR, Collins M, Mewett KN NH&MRC Project 2006-2008 GABA Modulators for the treatment of anxiety epilepsy and insomnia $529500.
    2. McLeod M, Collins M ARC Discovery 2006-2008 Elucidating the mode of action of nicotinic receptor ligands $275000.
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Past Sudents: Where are they now?

Jane Carland
Neurosciences Institute, University of Dundee, Scotland

Deborah Crittenden
Research School of Chemistry, Australian National University

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Recent Publications (2003-2007)

  • Book chapter and reviews
    1. Johnston GAR, Hanrahan JR, Chebib M, Duke RK, Mewett KN (2006) Modulation of ionotropic GABA receptors by natural products of plant origin. Adv Pharmacol 54, 285-316.
    2. Chebib M, Hanrahan JR, Mewett KN, Duke RK, Johnston GAR (2004) Ionotropic GABA receptors as therapeutic targets for memory and sleep disorders. Ann Reports Med Chem 39, 13-23.
    3. Chebib M (2004) GABAC receptor ion channel. Clin Exp Pharmacol Physiol 31, 800-04 [IF = 1.78].
    4. Johnston GAR, Chebib M, Hanrahan JR, Mewett KN (2003) GABAC receptors as drug targets. Curr Drug Targets: CNS & Neurological Disorders 2(4), 260-68 [IF = 4.274].
  • Refereed articles
    5. Abdel Halim H, Hanrahan JR, Hibbs DE, Johnston GAR, Chebib M (2008) A molecular basis for agonist and antagonist actions at GABAC receptors. Chem Biol Drug Des (New Wiley-Blackwell journal: accepted 1 February 2008).
    6. Carland JE, Johnston GAR and Chebib M (2008) Relative impact of residues at the intracellular and extracellular ends of the human GABAC rho1 receptor M2 domain on picrotoxinin activity. Eur J Pharmacol 580(1-2), 27-35 [IF = 2.522].
    7. Hinton T, Chebib M, Johnston GAR (2008) Enantioselective actions of 4-amino-3-hydroxybutanoic acid and (3-amino-2-hydroxypropyl)methylphosphinic acid at recombinant GABAC receptors. Bioorg Med Chem Lett 18(1), 402-04 [IF = 2.538].
    8. Chebib M, Hanrahan JR, Wooller S, Morriss G, Kumar RJ, Mewett KN, Johnston GAR (2007) (3-Aminocyclopentyl)methylphosphinic acids: Novel GABAC receptor antagonists. Neuropharmacol 52, 779-87 [IF = 3.86].
    9. Small DH, Maksel D, Kerr ML, Ng J, Hou X, Chu C, Mehrani H, Unabia S, Azari MF, Loiacono R, Aguilar M-I and Chebib M (2007) The b-amyloid protein of Alzheimer's disease binds to membrane lipids but does not bind to the _7 nicotinic acetylcholine receptor. J Neurochem 101(6), 1527-38 [IF = 4.26].
    10. Crittenden DL, Park, A, Qiu J, Silverman RB, Duke RK, Johnston GAR, Jordan MJT, Chebib M (2006) Enantiomers of cis-constrained and flexible 2-substituted GABA analogues exert opposite effects at recombinant GABAC receptors. Bioorg Med Chem 14, 447-55 [IF = 2.624].
    11. Hanrahan JR, Mewett KN, Chebib M, Matos S, Eliopoulos CT, Crean C, Kumar RJ, Burden P, Johnston GAR (2006) Diastereoselective synthesis of (±)-(3-aminocyclopentanyl)alkylphosphinic acids, conformationally restricted analogues of GABA. Org Biomol Chem 4 (13), 2642-49 [IF = 2.874].
    12. Halliday J, Chebib M, Turner P, McLeod MD (2006) Double-Mannich annulation of cyclic ketones using N,N-bis(ethoxymethyl)alkylamine reagents. Org Lett 8(15), 3399-3401 [IF = 4.659].
    13. Huang SH, Duke RK, Chebib M, Sasaki K, Wada K, Johnston GAR (2006) Mixed antagonistic effects of bilobalide at rho1 GABAC receptors. Neurosci 137, 607-17 [IF = 3.427].
    14. Crittenden DL, Chebib M, Jordan MJT. (2005) A quantitative structure-activity relationship investigation into agonist binding at GABAC receptors J Mol Struc THEOCHEM 755, 81-89 [IF = 1.016].
    15. Crittenden DL Kumar RJ, Hanrahan JR, Chebib M, Jordan MJT (2005) Stabilization of Zwitterions in Solution: Phosphinic and Phosphonic Acid GABA Analogues. J Phys Chem A 109(37), 8398-09 [IF = 3.047].
    16. Barker D, Lin DH-S, Carland JE, Chu CP-Y, Chebib M, Brimble MA, Savage GP, McLeod MD (2005) Methyllycaconitine analogues have mixed antagonist effects at nicotinic acetylcholine receptors. Bioorg Med Chem 13(14), 4565-75 [IF = 2.624].
    17. Hall BJ, Chebib M, Hanrahan JR, Johnston GAR (2005) 6-Methylflavanone, a more efficacious positive allosteric modulator of _-aminobutyric acid (GABA) action at human recombinant ______L than at ______L and ____ GABAA receptors expressed in Xenopus oocytes. Eur J Pharmacol 512(2-3), 97-104 [IF = 2.522].
    18. Crittenden DL, Chebib M, Jordan MJT (2005) Stabilization of zwitterions in solution: GABA analogues. J Phys Chem A 109(18), 4195-4201 [IF = 3.047].
    19. Campbell EL, Chebib M, Johnston GAR (2004) The dietary flavonoids apigenin and (-)-epigallocatechin gallate enhance the positive modulation by diazepam of the activation by GABA of recombinant GABAA receptors. Biochem Pharmacol 68(8), 1631-38 [IF = 3.581].
    20. Huang SH, Duke RK, Chebib M, Sasaki K, Wada K, Johnston GAR (2004) Ginkgolides, diterpene trilactones of Ginkgo biloba, as antagonists at recombinant alpha1, beta2, gamma2L GABAA receptors. Eur J Pharmacol 494, 131-38 [IF = 2.522].
    21. Carland JE, Moorhouse AJ, Barry PH, Johnston GAR, Chebib M (2004) Charged residues at the 2' position of human GABAC (1 receptors invert ion selectivity and influence open state probability. J Biol Chem 279, 54153-60 [IF = 5.808].
    22. Duke RK, Chebib M, Hibbs DE, Mewett KN, Johnston GAR (2004) Synthesis and resolution of 2-methyl analogues of GABA. Tett Asymm 15(11), 1745-51 [IF = 2.468].
    23. Small DH, Fodero LR, Losic D, Chu C, Aguilar M-I, Martin LL, Chebib M (2004) Binding of the amyloid peptide A_ to the _7 nicotinic acetylcholine receptor: implications for the regulation of synaptic plasticity in Alzheimer's disease. Lett Peptide Sci 10 (5), 401-04.
    24. Crittenden DL, Thompson KC, Chebib M, Jordan MJT (2004) Efficiency considerations in the construction of interpolated potential energy surfaces for the calculation of quantum observables by Diffusion Monte Carlo. J Phys Chem A 121 (20), 9844-54 [IF = 3.047].
    25. Hall BJ, Chebib M, Hanrahan JR, Johnston GAR (2004) Flumazenil-independent positive modulation of GABA action by 6-methylflavone at human recombinant ______L and ____ GABAA receptors. Eur J Pharmacol 491(1), 1-8 [IF = 2.522].
    26. Carland JE, Moore A, Hanrahan JR, Mewett KN, Duke RK, Johnston GAR, Chebib M (2004) Mutations of the 2' proline in the M2 domain of the human GABAC _1 subunit alter agonist responses. Neuropharmacol 46(6), 770-81 [IF = 3.86].
    27. Crittenden DL, Chebib M, Jordan MJT (2004) Stabilization of zwitterions in solution: _-Aminobutyric acid (GABA). J Phys Chem A, 108(1), 203-11 [IF = 3.047].
    28. Krehan D, Frolund B, Ebert B, Nielsen B, Krogsgaard-Larsen P, Johnston GAR, Chebib M (2003) Aza-THIP and related analogues of THIP as GABAC antagonists. Bioorg Med Chem 11(23), 4891-96 [IF = 2.624].
    29. Hanrahan JR, Chebib M, Davucheron NLM, Hall BJ, Johnston GAR (2003) Semisynthetic preparation of amentoflavone: a negative modulator at GABAA receptors. Bioorg Med Chem Lett 13(14), 2281-84 [IF = 2.538].
    30. Chebib M, Duke RK, Duke CC, Connor M, Mewett KN, Johnston GAR (2003) Convulsant actions of calycanthine. Tox App Pharmacol 190(1), 58-64 [IF = 4.722].
    31. Huang SH, Duke RK, Chebib M, Sasaki K, Wada K, Johnston GAR (2003) Bilobalide, a sesquiterpene trilactone from Ginkgo biloba, is an antagonist at recombinant ______L GABAA receptors. Eur J Pharmacol 464(1), 1-8 [IF = 2.522].
    32. Krehan D, Frolund B, Krogsgaard-Larsen P, Kehler J, Johnston GAR, Chebib M (2003) Phosphinic, phosphonic and seleninic acid bioisosteres of isonipecotic acid as novel and selective GABAC receptor antagonists. Neurochem Int 42(7), 561-65 [IF = 3.159].
  • Other refereed publication
    33. Johnston GAR, Chebib M, Duke RK, Fernandez SP, Hanrahan JR, Hinton T, Mewett KN (2008) Herbal products and ionotropic GABA receptors New Encyclopedia of Neuroscience, edited by L Squire, Elsevier, accepted 29.8.07
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Patents

  1. 1. McLeod MD, Halliday JI, Chebib M. Process for the preparation of compounds containing an azacyclic ring system. PCT Int. Appl. (2007) 87 pp. WO 2007051255.
    2. Chebib M, Kumar RJ, Johnston GAR, Hanrahan JR. Preparation of 4-amino-1-cyclopentenylphosphinates as neurologically-active specific antagonists for gamma-aminobutyric acid GABAC receptors. PCT Int. Appl. (2006) 44 pp WO 2006000043.
    3. Chebib M, Johnston GAR, Hanrahan JR Neurologically-active compounds. PCT Int. Appl. (2003) 69 pp WO 0345897.
    4. Johnston GAR, Burden PM, Mewett KN, Chebib M. Neurologically active phosphinic acid compound GABAC receptor antagonists, therapeutic methods, and compositions. PCT Int. Appl. (1998) 41 pp WO 9858939.
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