CHEMICAL AND PHARMACOLOGICAL CHARACTERIZATION OF GALANTHAMINE, AN ACETYLCHOLINESTERASE INHIBITOR, AND ITS DERIVATIVES - A POTENTIAL APPLICATION IN ALZHEIMERS-DISEASE

We conducted structural and pharmacological studies of galanthamine, a cortical acetylcholinesterase (AChE) inhibitor, and 19 structural analogs. Systematic derivatization of galanthamine at the cyclohexene ring, tertiary amino, hydroxyl and methoxyl functions indicated that these structural features are essential for biological activity. Molecular modeling studies suggested that the low energy conformations of the analogs are similar to that of the parent. One derivative, galanthamine n-butyl carbamate, had an LD50 of over 100 mg/kg (ip) in mice. In a passive avoidance paradigm, this analog improved performance in a dose-dependent fashion with a peak effect at 0.1 mg/kg in control and 0.5 mg/kg in basal forebrain lesioned mice. In the same paradigm, the peak effect of the parent compound is a 6-fold higher dose. With this surprinsingly high therapeutic ratio, this compound may be of interest in treating cholinergic deficits of the central nervous system such as Alzheimer's disease.