Identification of selective agonists and antagonists to g protein-activated inwardly rectifying potassium channels: candidate medicines for drug dependence and pain.

G protein-activated inwardly rectifying K(+) (GIRK) channels have been known to play a key role in the rewarding and analgesic effects of opioids. To identify potent agonists and antagonists to GIRK channels, we examined various compounds for their ability to activate or inhibit GIRK channels. A total of 503 possible compounds with low molecular weight were selected from a list of fluoxetine derivatives at Pfizer Japan Inc. We screened these compounds by a Xenopus oocyte expression system. GIRK1/2 and GIRK1/4 heteromeric channels were expressed on Xenopus laevis oocytes at Stage V or VI. A mouse IRK2 channel, which is another member of inwardly rectifying potassium channels with similarity to GIRK channels, was expressed on the oocytes to examine the selectivity of the identified compounds to GIRK channels. For electrophysiological analyses, a two-electrode voltage clamp method was used. Among the 503 compounds tested, one compound and three compounds were identified as the most effective agonist and antagonists, respectively. All of these compounds induced only negligible current responses in the oocytes expressing the IRK2 channel, suggesting that these compounds were selective to GIRK channels. These effective and GIRK-selective compounds may be useful possible therapeutics for drug dependence and pain.