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First published on September 29, 2008; DOI: 10.1124/mol.108.050567

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Received for publication July 15, 2008.
Revised September 25, 2008.
Accepted for publication September 25, 2008.

THIOPHENECARBOXYLATE SUPPRESSOR OF CYCLIC NUCLEOTIDES DISCOVERED IN A SMALL-MOLECULE SCREEN BLOCKS TOXIN-INDUCED INTESTINAL FLUID SECRETION

Lukmanee Tradtrantip 1, Buranee Yangthara 1, Prashant Padmawar 1, Christopher Morrison 1, Alan S. Verkman 1*

1 University of California, San Francisco

* Address correspondence to: E-mail: alan.verkman{at}ucsf.edu

Abstract

We carried out a 'pathway' screen of 50,000 small molecules to identify novel modulators of cAMP signaling. One class of compounds, the 2-(acylamino)-3-thiophenecarboxylates, strongly suppressed cAMP and cGMP in multiple cell lines in response to different agonists acting on G-protein coupled receptors, adenylyl cyclase and guanylyl cyclase. The best compounds from structure-activity analysis of 124 analogs, including several synthesized chiral analogs, had IC50 of <5 µM for suppression of agonist-induced cAMP and cGMP elevation. Measurements of cAMP, cGMP and downstream signaling in response to various activators/inhibitors suggested that the 2-(acylamino)-3-thiophenecarboxylates function as non-selective phosphodiesterase activators, though it was not determined whether their action on phosphodiesterases is direct or indirect. The 2-(acylamino)-3-thiophenecarboxylates suppressed CFTR-mediated Cl- current in T84 colonic cells in response to cholera and E. coli (STa) toxins, and prevented intestinal fluid accumulation in a closed-loop mouse model of secretory diarrhea. They also prevented cyst growth in an in vitro renal epithelial cell model of polycystic kidney disease. The 2-(acylamino)-3-thiophenecarboxylates represent the first small-molecule cyclic nucleotide suppressors, whose potential therapeutic indications include secretory diarrheas, polycystic kidney disease and growth inhibition of cAMP-dependent tumors.


Key words: cAMP, cGMP, Phosphodiesterases, Ion transporters (SERCA, Na/K ATPase, CFTR), Fluorescence techniques


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