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.

Links

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