PT  - JOURNAL ARTICLE
AU  - Cristiano G. Ponte
AU  - Owen B McManus
AU  - William A Schmalhofer
AU  - Dong-Ming Shen
AU  - Ge Dai
AU  - Andra Stevenson
AU  - Sylvie Sur
AU  - Tarak Shah
AU  - Laszlo Kiss
AU  - Min Shu
AU  - James B Doherty
AU  - Ravi Nargund
AU  - Gregory J Kaczorowski
AU  - Guilherme Suarez-Kurtz
AU  - Maria L Garcia
TI  - Selective, Direct Activation of High-conductance, Calcium-activated Potassium Channels Causes Smooth Muscle Reaxation
AID  - 10.1124/mol.111.075853
DP  - 2012 Jan 01
TA  - Molecular Pharmacology
PG  - mol.111.075853
4099  - http://molpharm.aspetjournals.org/content/early/2012/01/12/mol.111.075853.short
4100  - http://molpharm.aspetjournals.org/content/early/2012/01/12/mol.111.075853.full
AB  - High-conductance calcium-activated potassium (Maxi-K) channels are present in smooth muscle where they regulate tone. Activation of Maxi-K channels causes smooth muscle hyperpolarization and shortening of action potential duration which would limit calcium entry through voltage-dependent calcium channels leading to relaxation. Although Maxi-K channels appear to indirectly mediate the relaxant effects of a number of agents, activators that bind directly to the channel with appropriate potency and pharmacological properties useful for proof of concept studies are not available. Most agents identified to date display significant poly-pharmacy which severely compromises interpretation of experimental data. In the present study, a high-throughput, functional, cell-based assay for identifying Maxi-K channel agonists was established and used to screen a large sample collection (>1.6 M compounds). Based on potency and selectivity, a family of tetrahydroquinolines was further characterized. Medicinal chemistry efforts afforded identification of compound X, from which its two enantiomers, Y and Z, were resolved. In in vitro assays, Z is more potent than Y as a channel activator. The same profile is observed in tissues where the ability of either agent to relax pre-contracted smooth muscles, via a potassium channel-dependent mechanism, is demonstrated. These data, taken together, suggest that direct activation of Maxi-K channels represents a mechanism to be explored for the potential treatment of a number of diseases associated with smooth muscle hyper-excitability.