Development of a novel neuroprotective drug (TV3326) for the treatment of Alzheimer's disease, with cholinesterase and monoamine oxidase inhibitory activities

Abstract

TV3326 [(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate] is a novel aminoindan derivative possessing both cholinesterase (ChE) and monoamine oxidase (MAO)-inhibitory activity. In doses of 35–100 μmol/kg administered orally to rats, it inhibits ChE by 25%–40% and antagonises scopolamine-induced impairments in spatial memory. After daily oral administration of 75 μmol/kg for 2 weeks, TV3326 inhibits MAO-A and -B in the brain by ∼80% but has little or no effect on the enzymes in the intestine or liver. This reduces the likelihood of it producing the “cheese effect” if administered with tyramine-containing foods or beverages. TV3326 has activity in the forced-swim test, consistent with that of known antidepressants. Both TV3326 and its S- isomer, TV3279, which inhibits ChE but lacks MAO-inhibitory activity, have neuroprotective effects against a variety of insults in PC12 cells and in vivo. TV3326 significantly reduces hippocampal cell damage caused by global ischaemia in gerbils and the cerebral oedema induced by closed head injury in mice and speeds recovery of their motor and memory deficits. These pharmacological actions of TV3326 could clearly be of clinical importance for the treatment of Alzheimer's disease, and the drug is currently in development for this purpose. Drug Dev. Res. 50:216–222, 2000. © 2000 Wiley-Liss, Inc.