title: 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.
authors.affiliation: Pharmaceutical Chemistry and Centre for Human Metabonomics, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa.
authors.forename: Hendrik J R
authors.initials: HJ
authors.lastname: Lemmer
authors.forename: Jacques
authors.initials: J
authors.lastname: Joubert
authors.forename: Sandra
authors.initials: S
authors.lastname: van Dyk
authors.forename: Francois H
authors.initials: FH
authors.lastname: van der Westhuizen
authors.forename: Sarel F
authors.initials: SF
authors.lastname: Malan
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D015394:Molecular Structure; D009569:Nitric Oxide / Q000737:chemistry; D011084:Polycyclic Aromatic Hydrocarbons / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D011084:Polycyclic Aromatic Hydrocarbons; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D002118:Calcium