TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer's disease
by
Weinstock M, Bejar C, Wang RH, Poltyrev T,
Gross A, Finberg JP, Youdim MB.
Department of Pharmacology,
Hebrew University Hadassah School of Medicine,
Ein Kerem, Jerusalem, Israel.
martar@cc.huji.ac.il
J Neural Transm Suppl. 2000;(60):157-69


ABSTRACT

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.


MAOIs
Rasagiline
Neuroprotection
Ladostigil: structure
Rasagiline: structure
MAO-b inhibitors/PD
Anti-apoptotic activity
Molecular mechanisms
Rasagiline pharmacology
Induction of pro-survival genes
Antioxidant strategies against aging
Anti-Alzheimer/anti-Parkinson's drugs
Rasagiline versus selegiline metabolites
Dual AChE and MAO inhibitors and Alzheimer's
Rasagiline v selegiline: neuronal survival effects
Rasagiline (Agilect) in early Parkinson's disease
From rasagiline (Azilect) to ladostigil and the M30 HLA-20 series


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