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S-nitrosylation and attenuation of excessive calcium flux by pentacycloundecane derivatives.

Abstract

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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  • Publisher Full Text
  • Authors

    Lemmer HJ, Joubert J, van Dyk S, van der Westhuizen FH, Malan SF

    Institution

    Pharmaceutical Chemistry and Centre for Human Metabonomics, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa.

    Source

    Medicinal chemistry (Shāriqah (United Arab Emirates)) 8:3 2012 May pg 361-71

    MeSH

    Amines
    Animals
    Calcium
    Calcium Channel Blockers
    Calcium Channels
    Dose-Response Relationship, Drug
    Female
    Male
    Molecular Structure
    Nitric Oxide
    Polycyclic Hydrocarbons, Aromatic
    Rats
    Rats, Sprague-Dawley
    Receptors, N-Methyl-D-Aspartate
    Structure-Activity Relationship

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22530904