Cholinesterase inhibition by derivatives of 2-amino-4,6-dimethylpyridine.
Derivatives of 2-amino-4,6-dimethylpyridine, aryl(alkyl)carboxamides, thiocarbamides and amidrazones, already known for their anti-inflammatory properties, were found to be moderately active inhibitors of acetyl and butyrylcholinesterase. Quantitative structure-activity relationships showed that the binding affinity was enhanced by the following structural modifications: (1) increase in molecular volume, (2) decrease in the energy of the lowest unoccupied molecular orbital, (3) insertion of a methylene group between the amide carbonyl and the aromatic ring, (4) replacement of the amide oxygen by sulfur. The affinity remained, however, weaker than that of the specific inhibitor 9-amino-1,2,3,4-tetrahydroacridine (tacrine). The association of anti-inflammatory and cholinesterase inhibiting activities within the same compound may prove useful for the treatment of Alzheimer's disease.
Debord
J
J
Laboratoire de Pharmacologie, Faculté de Médecine, Limoges, France.
N'Diaye
P
P
Bollinger
J C
JC
Fikri
K
K
Penicaut
B
B
Robert
J M
JM
Robert-Piessard
S
S
Le Baut
G
G
D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000097:blood / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003198:Computer Simulation; D004593:Electrophorus; D006736:Horses; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D012984:Software; D013329:Structure-Activity Relationship
D000631:Aminopyridines; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase