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1: Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):33-8. Epub 2007 Dec 27.
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Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities.

Ruan B, Pong K, Jow F, Bowlby M, Crozier RA, Liu D, Liang S, Chen Y, Mercado ML, Feng X, Bennett F, von Schack D, McDonald L, Zaleska MM, Wood A, Reinhart PH, Magolda RL, Skotnicki J, Pangalos MN, Koehn FE, Carter GT, Abou-Gharbia M, Graziani EI.

Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA.

Rapamycin is an immunosuppressive immunophilin ligand reported as having neurotrophic activity. We show that modification of rapamycin at the mammalian target of rapamycin (mTOR) binding region yields immunophilin ligands, WYE-592 and ILS-920, with potent neurotrophic activities in cortical neuronal cultures, efficacy in a rodent model for ischemic stroke, and significantly reduced immunosuppressive activity. Surprisingly, both compounds showed higher binding selectivity for FKBP52 versus FKBP12, in contrast to previously reported immunophilin ligands. Affinity purification revealed two key binding proteins, the immunophilin FKBP52 and the beta1-subunit of L-type voltage-dependent Ca(2+) channels (CACNB1). Electrophysiological analysis indicated that both compounds can inhibit L-type Ca(2+) channels in rat hippocampal neurons and F-11 dorsal root ganglia (DRG)/neuroblastoma cells. We propose that these immunophilin ligands can protect neurons from Ca(2+)-induced cell death by modulating Ca(2+) channels and promote neurite outgrowth via FKBP52 binding.

PMID: 18162540 [PubMed - indexed for MEDLINE]

PMCID: PMC2224212