Development of a novel arylalkylpiperazine compound (AM-36) as a hybrid neuroprotective drug

Animal experimentation in recent years has revealed a complex biochemical c ascade after the induction of ischemia in brain as a model of the devastati ng disease, stroke. Drugs which block components of the biochemical cascade such as the depolarizing actions of the excitatory transmitter L-glutamate on its receptors have been investigated as putative neuroprotective drugs. Similarly antioxidants that quench free radicals that arise during ischemi a have also been investigated as putative neuroprotective drugs. We have de signed and synthesized a hybrid compound, AM-36 [1-(2-(4-chlorophenyl]-2-hy droxy)ethyl-4-(3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylpiperazine] to block several of the biochemical derangements during cerebral ischemia. Screening tests showed that AM-36 was able to block the polyamine site of glutamate receptors, neuronal sodium channels, and also was an antioxidant. Studies with neuronal cell cultures revealed that AM-36 blocked excitotoxi city induced both by N-methyl-D-aspartate (NMDA) as well as the sodium chan nel opener veratridine. in a realistic, conscious rat model of focal ischem ia, systemic injections of AM-36 substantially reduced the area of infarcti on in the cortex. AM-36 also protected striatal dopamine neurons in mice fr om excessive glutamatergic stimulation induced by subchronic injections of methamphetamine. These experiments in animals show that AM-36 is a unique n europrotective drug with more than one mechanism of action in preventing ne uronal degeneration. Drug Dev. Res. 46:261-267, 1999. (C) 1999 Wiley-Liss, Inc.