Joubert J., Dyk S.V., Green I.R., Malan S.F.
Pharmaceutical Chemistry, North-West University, Private Bag 6001, Potchefstroom 2520, South Africa; School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa; Department of Chemistry, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa
Joubert, J., Pharmaceutical Chemistry, North-West University, Private Bag 6001, Potchefstroom 2520, South Africa, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa; Dyk, S.V., Pharmaceutical Chemistry, North-West University, Private Bag 6001, Potchefstroom 2520, South Africa; Green, I.R., Department of Chemistry, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa; Malan, S.F., Pharmaceutical Chemistry, North-West University, Private Bag 6001, Potchefstroom 2520, South Africa, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa
A series of polycyclic fluorescent ligands were synthesised and evaluated in murine striatal synaptoneurosomes for N-methyl-d-aspartate receptor (NMDAR) mediated calcium flux inhibition and inhibition of calcium influx through voltage gated calcium channels (VGCC). Amantadine (a) and N-(1-adamantyl)-1,3- propanediamine (c) substituted with 1-cyanoisoindole (3), indazole (5), dinitrobenzene (7, 8), dansyl (9, 10) and coumarin (11) moieties showed moderate to high inhibition of the NMDAR. A high degree of VGCC inhibition was observed for the cyanoisoindole compounds (3, 4) the dansyl compounds (9, 10) and the coumarin compound (12). Fluorophores conjugated to hydroxy-4-aza-8- oxoheptacyclotetradecane (13, 14) did not exhibit any significant VGCC inhibition, but the indazole conjugate (14) showed promising NMDAR activity. Dose response curves were calculated for selected NMDAR inhibitors (8-11) and N-[3-(1-adamantylamino)propyl]-5-dimethylaminonaphthalene-1-sulfonamide (10) exhibited the highest activity of the novel compounds. Compound 10 was further used as a fluorescent NMDAR ligand in a fluorescent competition assay utilizing MK-801, NGP1-01 and amantadine as known NMDAR inhibitors to demonstrate the possible applications of the novel fluorescent compounds. These small molecule fluorescent ligands can be considered as possible pharmacological tools in assay development and/or other investigations in the study of neurodegeneration. © 2011 Elsevier Masson SAS. All rights reserved.
2 [3 (1 adamantylamino)propyl]isoindole 1 carbonitrile; 3 (1 adamantylamino)propionitrile; 3 [4 aza 8 oxo heptacyclo [0.4.1.0 2,10 .0 3,14 .0 4,9 . 09,13 .0 12,15]tetradecyl] 2 (methylamino)benzoate; 3 [4 Aza 8 oxo heptacyclo[0.4.1.0 2,10 .0 3,14 .0 4,9 . 09,13 .0 12,15]tetradecyl] 1h indazole 3 carboxylate; 3 hydroxy 4 aza 8 oxo heptacyclo[9.4.1.0 2,10 .0 3,14 .0 4,9 .0 12,15]tetradecane; amantadine derivative; dizocilpine; fluorescent dye; n (1 adamantyl) 1,3 propanediamine; n (1 adamantyl) 2 oxo chromene 3 carboxamide; n (1 cyano 2h isoindol 2 yl)adamantan 1 amine; n (2,4 dinitrophenyl)adamantan 1 amine; n (adamantan 1 yl) n' (2,4 dinitrophenyl)propane 1,3 diamiane; n [3 (1 adamantylamino)propyl] 1h indazole 3 carboxamide; n [3 (1 adamantylamino)propyl] 2 methylaminobenzamide; n [3 (1 adamantylamino)propyl] 5 dimethylaminonaphthalene 1 sulfonamide; n adamantan 1 yl 1h indazole 3 carboxamide; n adamantan 1 yl 2 (methylamino) benzamide; n adamantan 1 yl 5 dimethyl amino 1 naphthalenesulfonic acid; n methyl dextro aspartic acid receptor; unclassified drug; voltage gated calcium channel; animal cell; animal experiment; animal tissue; article; binding affinity; binding competition; brain synaptosome; calcium transport; concentration response; controlled study; drug binding site; drug receptor binding; drug screening; drug synthesis; fluorescence analysis; male; nonhuman; rat; receptor affinity; Amantadine; Animals; Calcium Channel Blockers; Calcium Channels; Fluorescent Dyes; Ligands; Male; Polycyclic Hydrocarbons, Aromatic; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synaptosomes