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Design, Synthesis and Evaluation of Centrally-Acting TRH Analogues
Collaborators: Professor Laszlo Prokai, Professor Nick Shaw and Dr Amitha Hewavitharana
In addition to its endocrine function, thyrotropin-releasing hormone (TRH, Pyr-His-Pro-NH2) is a modulatory neuropeptide in the central nervous system (CNS).1 The CNS activity of TRH and its analogues has stimulated interest in these peptides as prospective drugs for the treatment of motor neuron diseases, spinal cord trauma, and Alzheimer’s disease.2 A major hindrance to the development of TRH and its analogues as pharmaceuticals is their poor ability to cross the blood-brain barrier (BBB), which is attributed to TRH’s hydrophilicity (log P -2.46) and degradation by peptidases. This project will evaluate the CNS activity of novel TRH analogues and develop strategies to enhance the BBB permeability of these analogues, for the purpose of developing a TRH-based pharmaceutical product.
Increasing the lipophilicity of a hydrophilic drug can improve membrane partitioning and therefore increase BBB permeability. However, the lipophilic analogue can freely diffuse both into and out of the CNS and generally lipid-soluble compounds that are able to cross the BBB can maintain active concentrations in the CNS only if their blood concentrations are maintained at adequately high levels. A method of overcoming this problem is to design lipophilic prodrugs that are converted to hydrophilic drugs after crossing the BBB, thus trapping the drug in the CNS. The approach that the Ross Group uses is a Chemical Delivery System, whereby sequential metabolic or spontaneous transformations release the active drug within the CNS. A key step in this process is an initial rapid conversion of a lipophilic prodrug to a highly hydrophilic prodrug, which is trapped in the CNS and subsequently converted to the active drug. Site-specific metabolic conversion is desired to promote CNS targeting.
(1) Horita, A.; Carino, M. A.; Lai, H. Pharmacology of thyrotropin-releasing hormone. Annual review of pharmacology and toxicology 1986, 26, 311-332. (2) Prokai, L. Central nervous system effects of thyrotropin-releasing hormone and its analogues: opportunities and perspectives for drug discovery and development. Progress in Drug Research 2002, 59, 133-169.
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Latest News
10 April 2008 , New PhD student: Mr Manoj Kumar Palanivelu started his PhD today, funded by a prestigious Australian Government Endeavour Postgraduate Award. Manoj will focus on the design, synthesis and in vitro evaluation of inhibitors of amyloid aggregation.
25 January 2008, New PhD student: Welcome Mr Venkatesan Moorthy Rao who commenced his PhD today. Venky will develop prodrug strategies for the CNS delivery of inhibitors of beta-amyloid aggregation. Previously Venky was a Lecturer at the School of Pharmacy, International Medical University in KL, Malaysia.
18 October 2007, New Funding: A grant from the Clive and Vera Ramaciotti Foundations will support our research into Novel Anti-Amyloidogenic Therapies for Alzheimer's Disease.
3 October 2007, Honours and PhD applicants: Students who are considering Honours or PhD projects for 2008 should meet with Dr Ross to discuss their options.
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Contact
Dr Ben Ross School of Pharmacy The University of Queensland Brisbane, Queensland, 4072 AUSTRALIA
Phone: +61 7 336 58808 Fax: +61 7 336 51688
Email:
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This web site was last updated on 12 April 2008. Copyright © 2006-2008 Benjamin P. Ross. Unless stated otherwise, this web site represents only the views of Benjamin P. Ross and not the views of The University of Queensland. Simple site map. |
