title: Tricycloundecane Derivatives as Potential N-Methyl-D-aspartate (NMDA) Receptor and Voltage-Gated Calcium Channel Modulators.
abstract: Neurodegenerative disorders are debilitating conditions characterised by progressive dysfunction and death of neuronal cells. Amidst the proposed mechanisms of neurodegeneration, the effects of excitotoxicity via N-methyl-D-aspartate (NMDA) receptor stimulation and activation of voltage-gated calcium channels (VGCC) on neuronal cells are prominent. This has led to the development of polycyclic cage molecules such as NGP1-01, which exhibit neuroprotective properties through NMDA receptor and VGCC modulation. The medicinal potential of structurally related tricycloundecanes that are open-cage or rearranged polycyclic moieties has not been explored. This study is therefore focused on the synthesis of a series of novel tricycloundecane derivatives and their ability to inhibit NMDA receptors and VGCC. Significant NMDA receptor inhibition was observed for tricyclo[6.2.1.0(2,7) ]undec-9-ene-3,6-dione (4, 78%) and 6-hydroxytricyclo[6.2.1.0(2,7) ]undec-9-en-3-one (5, >95%) at a concentration of 100 μM. The highest inhibitory activity was observed for 6-(benzylimino)tricyclo[6.2.1.0(2,7) ]undec-9-en-3-one (9, >95%), which is in the same range as the inhibitory activity of MK-801 (dizocilpine). In the VGCC inhibition assay, 6-(benzylamino)tricyclo[6.2.1.0(2,7) ]undeca-4,9-dien-3-one (8, 34%), 9 (38%) and 2-(benzylamino)-3,6-epoxytricyclo[6.2.1.0(5,10) ]undecan-9-ol (12, 40%) showed statistically significant (p<0.05) VGCC inhibition.
authors.affiliation: School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535 (South Africa).
authors.forename: Ayodeji O
authors.initials: AO
authors.lastname: Egunlusi
authors.affiliation: School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535 (South Africa).
authors.forename: Sarel F
authors.initials: SF
authors.lastname: Malan
authors.affiliation: School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535 (South Africa). jjoubert@uwc.ac.za.
authors.forename: Jacques
authors.initials: J
authors.lastname: Joubert
mesh_terms: D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001952:Bridged-Ring Compounds; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D016194:Receptors, N-Methyl-D-Aspartate
keywords: N-methyl-D-aspartate receptors; neuroprotective agents; tricycloundecane; voltage-gated calcium channels