The central focus of this team is on the design and elucidation of the mechanism of action of novel mast cell stabilisers.
Mast cell derived mediators are now recognized not only as critical players in allergic conditions but also in tumour angiogenesis, rheumatoid arthritis, multiple sclerosis and coronary inflammation.
Mediator release from mast cells arises as a result of allergen-specific IgE production by B cells and the attachment of these newly formed IgE molecules onto the FceRI region of mast cells and basophils, thus sensitizing them. On further exposure of the same antigen, cross-linking of IgE molecules results in increased levels of intracellular calcium. A high level of intracellular calcium stimulates the release of many pro-inflammatory mediators such as histamine, leukotrienes and prostaglandins from these cells. It is the release of histamine, and the newly formed inflammatory mediators from mast cells and also basophils, often referred to as a “floating mast cell”, which gives rise to the clinical effects of allergic rhinitis, conjunctivitis, asthma and urticaria.
The team is working on the identification of novel and potent mast cell stabilisers that exhibit a wider distribution of pharmacological actions that those currently in use. They use a combination of natural product chemistry and synthetic organic chemistry to identify suitable candidate molecules while the efficacy of these compounds is performed in both in vitro and in vivo test systems. The team was originally focused on the isolation of the pterosin series of compounds or the synthesis of nature identical natural pterosins but has since expanded it armoury of compounds to include those whose architecture is centralised around the pterozin skeleton. Identifying the mechanism of action of these compounds is also one of the central activities of this group at present.
Head of Research Group
Members of the Research Group
Selected Publications and Patents
Synthesis and pharmacological activity of aminoindanone dimers and related compounds. Sheridan H, Butterly S, Walsh JJ, Cogan C, Jordan M, Nolan O, Frankish N. Bioorg Med Chem. 2008 Jan 1;16(1):248-54. Epub 2007 Sep 26.
Barlow JW, Walsh JJ, Synthesis and evaluation of 4-amino-3,4-dihydro-2H-naphthalen-1-one derivatives as mast cell stabilising and anti-inflammatory compounds, European Journal of Medicinal Chemistry, 43, (12), 2008, p2891 – 2900.
A.L. Simplício, J.F. Gilmer, N. Frankish, H. Sheridan, J.J. Walsh and J.M. Clancy, Ionisation characteristics and elimination rates of some aminoindanones determined by capillary electrophoresis, Journal of Chromatography A, 1045, (1-2), 2004, p233 – 238.
H.Sheridan, N. Frankish and R. Farrell, Investigation into the mast cell stabilizing activity of nature identical and synthetic indanones, J. Pharmacy and Pharmacology, 56, (11), 2004, p1423.
Patent: Walsh JJ, Frankish NF, Sheridan H, Byrne W, Jordan M. Indane compounds and their pharmaceutical use. US6433021, Publication date: 13-09-2002.
Patent: Walsh JJ, Frankish NF, Sheridan H, Byrne W. Indane dimer compounds with smooth muscle relaxing and/or mast cell stabilising and/or anti-inflammatory activity. US6423752, Publication date: 23-07-2002.
Patent: Walsh JJ, Frankish NF, Sheridan H, Byrne W. Indane compounds with smooth muscle relaxing and/or mast cell stabilising and/or anti-inflammatory activity. US6297399, Publication date : 02-10-2001.
Patent: Walsh JJ, Frankish NF, Sheridan H, Byrne W. Farrell R. Indane dimer compounds and their pharmaceutical use. US6300376: Publication date: 09-10-2001.