No abstract

A positional scanning library of N-alkylglycine trimers (peptoids) containing over 10 000 compounds has been synthesized on solid phase. The synthetic pathway involved the use of the submonomer strategy and a set of 22 commercially available primary amines as a chemical diversity source. The unbiased nature of the library allowed its screening against a variety of biological targets, leading to the identification of individual peptoids exhibiting remarkable biological activities (García-Martínez, C. et al. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 2374. Montoliu, et al. J. Pharm. Exp. Therap. 2002, 302, 29. Planells-Cases, R., et al. J. Pharm. Exp. Therap. 2002, 302, 163). In the present work, the screening of this library against a panel of Gram-positive and Gram-negative bacteria led to the identification of different compounds exhibiting antimicrobial activity.

Excitotoxicity has been implicated in the etiology of ischemic stroke and chronic neurodegenerative disorders. Hence, the development of novel neuroprotectant molecules that ameliorate excitotoxic brain damage is vigorously pursued. We used a neuroprotection-based cellular assay to screen a synthetic combinatorial library of N-alkylglycine trimers. Two compounds (6-1-2 and 6-1-10) that efficiently prevented excitotoxic neurodegeneration in vitro and in vivo were identified. Both molecules protected primary cultures of cerebellar neurons against glutamate-induced neuronal death with an efficiency equivalent to N-methyl-D-aspartate (NMDA) receptor antagonists. These trialkylglycines did not block appreciably the NMDA receptor channel, or attenuated glutamate-induced increase of Ca 2ϩ , or affect the glutamate-nitric oxide-cGMP pathway. Intraperitoneal injection of both peptoids in mice attenuated Ն80% ammonia-induced, NMDA receptor-mediated animal death. Furthermore, these two molecules reduced by Ն50% the neurodegeneration in striatum in a rat model of cerebral ischemia. Neuroprotection against ischemia was associated with decreased activation of caspase-3, reflecting prevention of apoptotic neuronal death. Collectively, the results reported indicate that these trialkylglycines are new neuroprotectant leads with important in vivo activity against excitotoxicity, and that they act on a novel, yet-unrecognized cellular target. These lead compounds may become tolerated drugs for the treatment of acute and chronic neurodegenerative diseases with fewer side effects than NMDA receptor antagonists.