Several novel norcamphor derivatives were designed and synthesized as uncompetitive NMDA receptor antagonists at the phencyclidine (PCP) binding site. Such compounds have potential as ligands for understanding and possibly the treatment of several neurodegenerative disorders and other glutamate-dependent disorders. We examined the toxic effects of the compounds as compared with memantine, an NMDA receptor antagonist that is FDA approved for treatment of Alzheimer’s disease, by testing these compounds on two cell lines: MDCK (to mimic blood brain barrier) and N2a (a neuronal cell line). The compounds showed toxicity profiles similar to those of memantine i.e., dose dependence above 100 μM and IC 50 values above 150 μM for each cell line. It is known that the serum level of memantine under therapeutic conditions in patients is about 1 μM, indicting these compounds could have acceptable therapeutic indexes. 2-Phenyl- N-(2-(piperidin-1-yl) ethyl)bicyclo[2.2.1]heptan-2-amine ( 5a) was found to possess acceptable toxicity profiles in both cell lines. Interestingly, this was the compound identified as a good lead in our previous studies based on binding and anticonvulsant (MES) activity studies. It has thus emerged as an excellent lead compound for further studies.
References
[1]
Mori, H.; Mishina, M. Structure and function of the NMDA receptor channel. Neuropharmacology 1995, 34, 1219–1237, doi:10.1016/0028-3908(95)00109-J.
[2]
Furukawa, H.; Singhl, S.K; Mancusso, R.; Gouaux, E. Subunit arrangement and function in NMDA receptors. Nature 2005, 438, 185–192.
[3]
Paoletti, P. Molecular basis of NMDA receptor functional diversity. Eur. J. Neurosci. 2011, 33, 1351–1365, doi:10.1111/j.1460-9568.2011.07628.x.
[4]
Cacabelos, R.; Takeda, M.; Winblad, B. The glutamatergic system and neurodegeneration in dementia: Preventive strategies in Alzheimer’s disease. Int. J. Geriatr. Psychiatry 1999, 14, 3–47, doi:10.1002/(SICI)1099-1166(199901)14:1<3::AID-GPS897>3.0.CO;2-7.
Fan, M.M.Y.; Raymond, L.A. N-methyl-d-aspartate (NMDA) receptor function and excitotoxicity in Huntington’s disease. Prog. Neurobiol. 2007, 81, 272–293, doi:10.1016/j.pneurobio.2006.11.003.
[7]
Parsons, C.G.; Danysz, W.; Quack, G. Glutamate in CNS disorders as a target for drug development: An updater. Drug News Perspect 1998, 11, 523–569, doi:10.1358/dnp.1998.11.9.863689.
[8]
Adejare, A. Non-Competitive NMDA Receptor Antagonists. USA Patent 8129414, 6 March 2012.
[9]
Mody, I.; MacDonald, J.F. NMDA receptor-dependent excitotoxicity: The role of intracellular Ca2+ release. Trends Pharmacol. Sci. 1995, 16, 356–359, doi:10.1016/S0165-6147(00)89070-7.
[10]
Sattler, R.; Tymianski, M. Molecular mechanisms of calcium-dependent excitotoxicity. J. Mol. Med. 2000, 78, 3–13, doi:10.1007/s001090000077.
[11]
Rothman, S.M.; Olney, J.W. Excitottoxicity and the NMDA receptor-still lethal after eight years. Trends Neurosci. 1995, 18, 57–58, doi:10.1016/0166-2236(95)93869-Y.
[12]
Chen, H-S.V.; Lipton, S.A. The chemical biology of clinically tolerated NMDA receptor antagonists. J. Neurochem. 2006, 97, 1611–1626, doi:10.1111/j.1471-4159.2006.03991.x.
[13]
Ogunbadeniyi, A.M.; Adejare, A. Syntheses of Fluorinated Phencyclidine Analogs. J. Fluor. Chem. 2002, 114, 39–42, doi:10.1016/S0022-1139(01)00565-6.
[14]
Buyukbingol, E.; Sisman, A.; Alparslan, F.; Adejare, A. Adaptive neuro-fuzzy inference system (ANFIS): A new approach to predictive modeling in QSAR applications: A study of neuro-fuzzy modeling of PCP-based NMDA Receptor Antagonists. Bioorg. Med. Chem. 2007, 15, 4265–4282, doi:10.1016/j.bmc.2007.03.065.
[15]
Gaye, B.; Adejare, A. Fluorinated Molecules in the diagnosis and treatment of neurodegenerative diseases. Future Med. Chem. 2009, 1, 821–833, doi:10.4155/fmc.09.85.
[16]
Erdas, O.; Buyukbingol, E.; Alpaslan, F.N.; Adejare, A. Modeling and predicting binding affinity of phencyclidine-like compounds using machine learning methods. J. Chemom. 2010, 24, 1–13.
[17]
Atez-Alagoz, Z.; Sun, S.; Wallach, J.; Adejare, A. Syntheses and pharmacological evaluation of novel N-substituted bicycle-heptane-2-amines at N-methyl-D-aspartate receptors. Chem. Biol. Drug. Des. 2011, 78, 25–32, doi:10.1111/j.1747-0285.2011.01124.x.
[18]
Wang, Q.; Rager, J.D.; Weinstein, K.; Kardos, P.S.; Dobson, G.L.; Li, J.; Hidalgo, I.J. Evaluation of the MDR-MDCK cell line as a permeability screen for the blood-brain barrier. Int. J. Pharm. 2005, 288, 349–359, doi:10.1016/j.ijpharm.2004.10.007.
[19]
Veronesi, B. Characterization of the MDCK cell line for screening neurotoxicants. Neurotoxicology 1996, 17, 433–443.
[20]
Kornhuber, J.; Quack, G. Cerebrospinal fluid and serum concentrations of the N-methyl-D-aspartate (NMDA) receptor antagonist memantine in man. Neurosci. Lett. 1995, 195, 137–139, doi:10.1016/0304-3940(95)11785-U.
[21]
Mosmann, T.J. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Immunol. Meth. 1983, 65, 55–63, doi:10.1016/0022-1759(83)90303-4.
