Biological activity profiles of selected polycyclic cage amines
Geldenhuys, Werner Jasper
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Parkinson's disease (PD) is a severe and debilitating age-related neurodegenerative disease, with symptoms of resting tremor, akinesia and rigidity. The symptoms of PD are due to the selective loss of dopaminergic neurons in the substantia nigra. Three drug targets were identified for this study aimed at developing new drugs for the symptomatic treatment and/or prevention of PD. These included the dopamine transporter (DAT), monoamine oxidase (MAO) B enzyme and the N-methyl-D-aspartate (NMDA) receptor/ion channel complex. In addition, the parent compound, NGP1-01 (1), was evaluated in two in vivo models of neurodegenerative disease, which included the MPTP Parkinsonian mouse model (as a model for chronic neurodegenerative processes) and a stroke model - middle artery occlusion (MCAO) induced focal cerebral ischemia model - in mice (as a model for acute neurodegenerative processes). Memantine is a polycyclic mine that is used clinically to treat PD and Alzheimer's disease. It is a low-affinity uncompetitive NMDA receptor antagonist and is well tolerated clinically. Antagonism of the NMDA receptor prevents Ca2+ overload in neuronal cells, thereby preventing neuronal cell death. The importance of Ca2+ in neuronal cell death led us to evaluate another polycyclic mine NGPl-01 (1) and its derivatives for possible Neuro protective activity. These compounds were previously characterized as L-type calcium channel antagonists. NGP1-01 (1) and its derivatives were evaluated for their effects on [3H]dopamine ([3H]DA) release and uptake Inhibition in murine striatal synaptosomes, as well as for inhibition of baboon liver monoamine oxidase (MAO) B. NGP1-01 (1) blocked the uptake of [3H]DA with an IC50 of 57 µM, while another compound, 8-phenylethyl- 8,11-oxapentacyclo[5.4.0.02,6.03,10.05,9]undecane(9), blocked uptake at an IC50 value of 23 µM. These values were comparable to that of amantadine (IC50; 82 µM), another polycyclic mine that is currently used in parkinsonian therapy. MAO-B inhibition for this group was weak, with less than 50% inhibition at 300 µM for any of the compounds in the series. NGP1-01 (1) and its derivatives were then further evaluated in a functional biochemical assay to assess NMDA antagonism. The IC50 values for the reference compounds MK-801 and memantine were 1.23µpM and 3.05 µM, respectively, for blocking NMDA-mediated 45Ca2+ influx into whole brain murine synaptoneurosomes. NGP1-01 (1) proved to be the most potent experimental compound with an IC5-0 of 2.98 µM, while 8-amino-pentacyclo[5.4.0.02,6.03,10.05,9]undecane (8) had a similar IC50 of 4.06 µM. NGP1-01 (1) was further shown to be a non-competitive NMDA antagonist. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques were used to provide models to predict the PCP binding affinity of NGP1-01 and other polycyclic mines on the NMDA receptor. The resulted r2 of the CoMFA and CoMSIA models were 0.976 and 0.883 respectively. Radioligand binding studies with [3H]MK-801 of [3H]TCP however, showed little or no displacement of the ligands by pentacycloundecylamines, indicating that they bind to a novel site on the NMDA receptor. Since NGP1-01 (1) was shown to have NMDA receptor antagonist activity, it was evaluated in a battery of behavioural tests in the MPTP-mouse model using retired breeder C57BL/6 male mice, to determine whether this compound might alleviate behaviour deficits in this model. The behavioural tests included fore-paw stride length, pole test (bradykinesia), catalepsy, rearing and movement. Biochemical confirmation of MPTP-induced toxicity was done by measuring striatal DA levels using HPLC with electrochemical detection while the amount of DAT present was determined by Western Blot. NGP1-01 was found to attenuate bradykinesia and catalepsy to a small extent. NGP1-01 (1) was also evaluated in the middle artery occlusion (MCAO) induced focal cerebral ischemia model in mice to evaluate the Neuro protective potential in stroke. In this study, NGP1-01 (1), at a dose of 20 mg/kg ip injected 30 min before MCAO, reduced the edema volume by 87%, and the infarct volume by 58%, compared to control. In conclusion, the pentacycloundecylamines represent a new class of compounds that might have utility in the prevention and/or treatment of neurodegenerative diseases through their interaction with a variety of drug targets involved in these diseases.
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