114301-53-0Relevant academic research and scientific papers
Structure-activity relationships of polycyclic aromatic amines with calcium channel blocking activity
Malan, Sarel F.,Van Der Walt, J. Jurgens,Van Der Schyf, Cornelius J. Der
, p. 10 - 16 (2000)
8-Benzylamino-8,11- oxapentacyclo[5.4.0.02,6.033,10.05,9]undecane (1) inhibits the calcium current in L-type calcium channels. A series of nitrobenzylamines (2, 3, 4), methoxybenzylamines (5,6, 7), methylpyridines (8, 9m 10), and a phenylhydrazine derivative (11) of 8,11- oxapentacyclo[5.4.0.02,6.03,105,9]undecane was synthesized. By substituting the 8,11-oxapentacyclo- [5.4.0.02,6.03,10.05,9]undecane skeleton with 3-hydroxyhexacyclo- [6.5.0.03,7.04,12.05,10.09,10]tridecane (12), 8,13- dioxapentacyclo[6.5.0.02,6.05,10.03.11]tridecane-9-one (13), and pentacyclo[5.4.0.02,6.03,10.05,9]undecane (14), the effect of the polycyclic skeleton could also be investigated. Increased inhibition of calcium current was observed with aromatic substitution (especially ortho and meta substitution) in the pentacycloundecane series. The calcium channel activities of the methoxy compounds were slightly higher than those of the corresponding nitro compounds while a definite decrease in activity was observed for the phenylhydrazine and aminomethylpyridine derivatives. Increased inhibition of the calcium current was also observed for structures in which the polycyclic 'cages' were enlarged. Structure-activity relationships in this series of compounds therefore appear to be dominated by geometric or steric constraints.
S-nitrosylation and attenuation of excessive calcium flux by pentacycloundecane derivatives
Lemmer, Hendrik J.R.,Joubert, Jacques,Van Dyk, Sandra,Van Der Westhuizen, Francois H.,Malan, Sarel F.
experimental part, p. 361 - 371 (2012/10/07)
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-Daspartate 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.
Physicochemical prediction of a brain-blood distribution profile in polycyclic amines
Zah, Jaco,Terre'Blanche, Gisella,Erasmus, Elardus,Malan, Sarel F.
, p. 3569 - 3578 (2007/10/03)
Recent investigation into the pharmacological character of the pentacyclo[5.4.0.02,6.03,10.05,9]undecyl and related polycyclic amines has revealed interesting facts regarding their possible use as neuroprotective agents. At this stage however, a clear shortcoming in the quest for further development of this novel class of compounds is the lack of concrete data on their ability to cross the blood-brain barrier (BBB). Working towards the aim of predicting BBB permeability, a series of related N-substituted 8-amino-8,11-oxapentacyclo[5.4.0.02,6.03,10.0 5,9]undecanes were synthesised. Compounds were characterised by both experimental and calculative methods, followed by biological assessment and statistical manipulation of the results obtained. In doing so, a simple biological model was established for the comparative evaluation of brain-blood distribution properties within the class. A highly sensitive ESI-MS.MS analytical procedure was developed for the detection of these compounds in biological tissues, indicating significant drug concentrations in the brain after intraperitoneal administration to C57Bl/6 mice. Stepwise multiple linear regression analysis of all data yielded two meaningful models (R2=0.9996 and R2=0.7749) depicting lipophilicity (log Poct), solvent accessible molecular volume (SV), molar refractivity (MR) and system energy as the prime determinants of the brain-blood profile for these amines. The inherently high lipophilicity potential within the series is attributed to strong hydrophobic influences dominating hydrogen bonding effects. A possible conformational and energy dependent preference at the site of permeation is also suggested. The proposed estimations allow for the expedient and reliable prediction of brain partitioning behaviour for related polycyclic amines, facilitating the early rejection of unsuitable candidates and enabling research to focus on neuroprotective activity.
