Identification of compounds that potentiate CREB signaling as possible enhancers of long-term memory - PubMed (original) (raw)

Identification of compounds that potentiate CREB signaling as possible enhancers of long-term memory

Menghang Xia et al. Proc Natl Acad Sci U S A. 2009.

Abstract

Many studies have implicated the cAMP Response Element Binding (CREB) protein signaling pathway in long-term memory. To identify small molecule enhancers of CREB activation of gene expression, we screened approximately 73,000 compounds, each at 7-15 concentrations in a quantitative high-throughput screening (qHTS) format, for activity in cells by assaying CREB mediated beta-lactamase reporter gene expression. We identified 1,800 compounds that potentiated CREB mediated gene expression, with potencies as low as 16 nM, comprising 96 structural series. Mechanisms of action were systematically determined, and compounds that affect phosphodiesterase 4, protein kinase A, and cAMP production were identified, as well as compounds that affect CREB signaling via apparently unidentified mechanisms. qHTS followed by interrogation of pathway targets is an efficient paradigm for lead generation for chemical genomics and drug development.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Scaffolds of enhancers of the CREB signaling pathway. (A) Ten of 30 scaffolds we identified are shown. Each scaffold is identified by a number. (B) Six scaffolds of compounds with known biological activities are shown. In parentheses are shown the number of active compounds found over the total number of compounds from that scaffold screened.

Fig. 2.

Fig. 2.

Confirmation study for compounds from series 41, using the CRE β-lactamase assay. (A) Concentration response curves of selected compounds from series 41. (B) Structures of these compounds are shown with NCGC compound IDs and EC50 values.

Fig. 3.

Fig. 3.

Compounds from series scaffold 72 in the PDE4 enzyme assay. (A) Concentration response curves of selected compounds from series 72. (B) Structures of these compounds are shown with NCGC compound IDs and IC50 values. The scaffold for rolipram is 109a.

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