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Development of a novel arylalkylpiperazine compound (AM‐36) as a hybrid neuroprotective drug
Author(s) -
Jarrott Bevyn,
Callaway Jennifer K.,
Jackson W. Roy,
Beart Philip M.
Publication year - 1999
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199903/04)46:3/4<261::aid-ddr11>3.0.co;2-q
Subject(s) - neuroprotection , excitotoxicity , glutamate receptor , pharmacology , ischemia , glutamatergic , nmda receptor , veratridine , chemistry , neuroscience , sodium channel , medicine , receptor , biology , biochemistry , sodium , organic chemistry
Animal experimentation in recent years has revealed a complex biochemical cascade after the induction of ischemia in brain as a model of the devastating 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 ischemia have also been investigated as putative neuroprotective drugs. We have designed and synthesized a hybrid compound, AM‐36 [1‐(2‐(4‐chlorophenyl]‐2‐hydroxy)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 excitotoxicity induced both by N‐methyl‐D‐aspartate (NMDA) as well as the sodium channel opener veratridine. In a realistic, conscious rat model of focal ischemia, systemic injections of AM‐36 substantially reduced the area of infarction in the cortex. AM‐36 also protected striatal dopamine neurons in mice from excessive glutamatergic stimulation induced by subchronic injections of methamphetamine. These experiments in animals show that AM‐36 is a unique neuroprotective drug with more than one mechanism of action in preventing neuronal degeneration. Drug Dev. Res. 46:261–267, 1999. © 1999 Wiley‐Liss, Inc.