TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer's disease.
TV3326, [(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate] is a novel aminoindan derivative of the selective irreversible monoamine oxidase (MAO)-B inhibitor, rasagiline (N-propargyl-(1R)-aminoindan), possessing both cholinesterase (ChE) and MAO-inhibitory activity. In doses of 35-100 micromoles/kg administered orally to rats, it inhibits ChE by 25-40% and antagonises scopolamine-induced impairments in spatial memory. After daily administration of 75 micromoles/kg for 2 weeks, TV3326 does not show any motor stimulant effects but significantly reduces immobility in the forced swim test, an action consistent with that of known antidepressants. This could result from more than 70% inhibition of both MAO-A and B in the brain that occurs under these conditions, since it is not shared by the S-isomer, TV3279, which does not block MAO. TV3326 also shows selectivity for brain MAO, even after 2 months of daily administration, with little or no effect on the enzyme in the intestinal tract and liver. This reduces the likelihood of it producing the "cheese effect" if administered with tyramine-containing foods or beverages. TV3326 and TV3279 protect against ischemia-induced cytotoxicity in PC12 cells and reduce the oedema, deficits in motor function and memory after closed head injury in mice. These neuroprotective effects do not result from MAO inhibition. The pharmacological actions of TV3326 could be of clinical importance for the treatment of AD, and the drug is currently in development for this purpose.
Weinstock
M
M
Department of Pharmacology, Hebrew University Hadassah School of Medicine, Ein Kerem, Jerusalem, Israel. martar@cc.huji.ac.il
Bejar
C
C
Wang
R H
RH
Poltyrev
T
T
Gross
A
A
Finberg
J P
JP
Youdim
M B
MB
D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D000818:Animals; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D007189:Indans / Q000819:agonists* / Q000494:pharmacology*; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy; D008995:Monoamine Oxidase / Q000187:drug effects / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012601:Scopolamine / Q000037:antagonists & inhibitors
C423264:(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate; D002800:Cholinesterase Inhibitors; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; C031967:rasagiline; D012601:Scopolamine; D008995:Monoamine Oxidase; D000110:Acetylcholinesterase