| S-Nitrosylation and Attenuation of Excessive Calcium Flux by Pentacycloundecane Derivatives. | |
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MedLine Citation:
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PMID: 22530904 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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A novel series of polycyclic amines, containing nitrogen monoxide donating moieties, were synthesised and tested for calcium channel and N-methyl-D-aspartate receptor modulating activity. The synthesised compounds were classified into two groups, based on their nitrogen monoxide donating moieties: unsaturated nitro compounds (1, 2 and 3) and nitro esters, or nitrates (4, 5 and 6). The nitrates were obtained via the reaction of hydroxyl functionalities with thionylchloride nitrate. All of the compounds synthesised exhibited significant (p < 0.01) S-nitrosylation capacity. The calcium channel activity of the polycyclic amines was evaluated using a KCl mediated fluorescent calcium flux assay. All the compounds exhibited better calcium channel antagonism than the lead structure, NGP1-01, with compound 1 exhibiting calcium channel blockade comparable to the commercially available nimodipine at concentrations of 10 μM and 1 μM. Compounds 3 and 4 inhibited calcium flux to these levels at 10 μM concentrations. NMDA/glycine mediated N-methyl-D-aspartate receptor (NMDAR) calcium influx inhibition was evaluated at a 100 µM concentration using a fluorescent calcium flux assay. All the compounds exhibited NMDAR antagonism with compounds 1 (25.4 %), 2 (20.24 %), 3 (33.14 %) and 6 (24.55 %) showing the most significant NMDAR inhibitory activity (p < 0.01). No clear correlation was observed between the S-nitrosylation capabilities of the compounds and their calcium channel activity or NMDAR channel antagonism, indicating that other factors probably play a more decisive role in the mechanism of pentacycloundecylamine channel modulation. This could include the geometric and steric bulk considerations that have been described to contribute to the channel activities of the pentacycloundecylamines. All the compounds synthesised exhibited promising calcium channel and NMDAR channel inhibitory activity and show promise as potential lead compounds for drug development against neurodegeneration. |
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Authors:
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Hendrik; J R Lemmer; Jacques Joubert; Sandra van Dyk; Francois; H van der Westhuizen; Sarel F Malan |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-4-24 |
Journal Detail:
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Title: Medicinal chemistry (Shariqah (United Arab Emirates)) Volume: - ISSN: 1875-6638 ISO Abbreviation: - Publication Date: 2012 Apr |
Date Detail:
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Created Date: 2012-4-25 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101240303 Medline TA: Med Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville, 7535, South Africa. sfmalan@uwc.ac.za. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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