Side-Chain Hydrophobicity Controls the Activity of Proton Channel Forming Rigid Rod-Shaped Polyols

Increased activity, facile incorporation into lipid bilayers and intact active structure and transport selectivity are the consequences of modifications of the side-chain hydrophobicity of a proton channel-forming octa(p-phenylene)

Voltage-Dependent Ion Channel Formation by Rigid Rod-Shaped Polyols in Planar Lipid Bilayers

In this Letter, we describe the appearance of large, voltage-dependent currents in BLM induced by rigid rodshaped polyols that function without charge and permanent dipole moment. The capacity of these symmetrical, nonpeptide models to form either short-living nanopores or small ion channels is shown to depend critically on the length of rigid-rod scaffold as well as the nature of the lateral side chains

Rigid Rod-Shaped Polyols: Functional Nonpeptide Models for Transmembrane Proton Channels

The present study concerns the mode of action of a rigid rod-shaped polyol 1 and the corresponding hexamer 2. Proton flux mediated by 1 is shown to be strongly favored over metal cations and anions. The modest selectivity for monovalent cations (Rb+ > Cs+ > K+ > Na+ ˜ Li+, Eisenman sequence II) is determined by the dehydration energy and is weakly influenced by the local electric (ionophoric) field. The induction of membrane defects was ruled out by the absence of dye leakage. Structural studies by circular dichroism and fluorescence spectroscopy imply that 1 aggregates in polar and nonpolar solvents, but not in lipid bilayers. Furthermore, it is shown that a very small fraction of 1 adopts a monomeric transmembrane tunnel-like structure which accounts for activity, while the remainder forms inactive self-assemblies. The above results suggest that 1 acts as a functional unimolecular proton wire which mimics the hydrogen-bonded chain mechanism found in bioenergetic systems

Structure–Activity Relationship Studies and Discovery of a Potent Transient Receptor Potential Vanilloid (TRPV1) Antagonist 4‑[3-Chloro-5-[(1<i>S</i>)‑1,2-dihydroxyethyl]-2-pyridyl]‑<i>N</i>‑[5-(trifluoromethyl)-2-pyridyl]-3,6-dihydro‑2<i>H</i>‑pyridine-1-carboxamide (V116517) as a Clinical Candidate for Pain Management

A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expressing human TRPV1. The most potent of these TRPV1 antagonists were further characterized in pharmacokinetic, efficacy, and body temperature studies. On the basis of its pharmacokinetic, in vivo efficacy, safety, and toxicological properties, compound <b>37</b> was selected for further evaluation in human clinical trials