TY - JOUR T1 - Molecular Requisites for Drug Binding to Muscle CLC-1 and Renal CLC-K Channel Revealed by the Use of Phenoxy-Alkyl Derivatives of 2-(<em>p</em>-Chlorophenoxy)Propionic Acid JF - Molecular Pharmacology JO - Mol Pharmacol SP - 265 LP - 271 DO - 10.1124/mol.62.2.265 VL - 62 IS - 2 AU - Antonella Liantonio AU - Alessio Accardi AU - Giuseppe Carbonara AU - Giuseppe Fracchiolla AU - Fulvio Loiodice AU - Paolo Tortorella AU - Sonia Traverso AU - Patrizia Guida AU - Sabata Pierno AU - Annamaria De Luca AU - Diana Conte Camerino AU - Michael Pusch Y1 - 2002/08/01 UR - http://molpharm.aspetjournals.org/content/62/2/265.abstract N2 - CLC channels are a gene family of Cl− channels that serve a variety of functions, several of which are involved in genetic diseases. Few specific ligands of CLC channels are known that could be useful as pharmacological tools or potential drugs. We synthesized various derivatives of 2-(p-chlorophenoxy)propionic acid, the S(−)-enantiomer of which is a specific blocker of the muscle channel CLC-1. In particular, compounds with different alkyl or phenoxy-alkyl groups on the chiral center, isosteres of the oxygen in the aryloxy moiety, or bioisosteres of the carboxy function were prepared. We found that compounds containing a phenoxy and a phenoxy-alkyl group on the chiral center (bis-phenoxy derivatives) specifically inhibited renal CLC-K channels from the extracellular side with an affinity in the 150-μM range and with almost no effect on other CLC channels when applied from the outside. Surprisingly, the same substances inhibited CLC-1 from the intracellular side in a voltage-dependent manner with an apparentK D of &lt;5 μM at −140 mV, thus being the most potent blockers of a CLC channel known so far. Although the chlorine atom in para- position of the second phenoxy group was essential for inhibition of CLC-K channels from the outside, it could be substituted by a methoxy group without changing the potency of block for CLC-1 from the inside. These newly identified substances provide powerful tools for studying the structure-function relationship and the physiological role of CLC channels and may represent a starting point for the development of useful drugs targeting CLC-K channels. ER -