KCNQ2/3 openers show differential selectivity and site of action across multiple KCNQ channels.

KCNQ2/3 voltage-gated potassium channels conduct low-threshold, slowly activating and non-inactivating currents to repolarize the neuronal resting membrane potential. The channels negatively regulate neuronal excitability and KCNQ2/3 openers are efficacious in hyperexcited states such as epilepsy and pain. We developed and utilized thallium influx assays to profile novel KCNQ2/3 channel openers with respect to selectivity across KCNQ subtypes and on requirement for tryptophan 236 of KCNQ2, a critical residue for activity of the KCNQ opener retigabine.

Synthesis and in vitro activity of N-benzyl-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine P2X(7) antagonists.

Synthesis and biological evaluation of a novel class of substituted N-benzyl-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine derivatives resulted in the identification of potent P2X(7) antagonists. These compounds were assayed for activity at both the human and rat P2X(7) receptors. On the benzyl moiety, a variety of functional groups were tolerated, including both electron-withdrawing and electron-donating substituents.

The antihyperalgesic activity of a selective P2X7 receptor antagonist, A-839977, is lost in IL-1alphabeta knockout mice.

The pro-inflammatory cytokine interleukin-1beta (IL-1beta) has been implicated in both inflammatory processes and nociceptive neurotransmission. Activation of P2X7 receptors is the mechanism by which ATP stimulates the rapid maturation and release of IL-1beta from macrophages and microglial cells. Recently, selective P2X7 receptor antagonists have been shown to reduce inflammatory and neuropathic pain in animal models.

Discovery and biological evaluation of novel cyanoguanidine P2X(7) antagonists with analgesic activity in a rat model of neuropathic pain.

We disclose the design of a novel series of cyanoguanidines that are potent (IC(50) approximately 10-100 nM) and selective (> or = 100-fold) P2X(7) receptor antagonists against the other P2 receptor subtypes such as the P2Y(2), P2X(4), and P2X(3). We also found that these P2X(7) antagonists effectively reduced nociception in a rat model of neuropathic pain (Chung model). Particularly, analogue 53 proved to be effective in the Chung model, with an ED(50) of 38 micromol/kg after intraperitoneal administration.

[3H]A-804598 ([3H]2-cyano-1-[(1S)-1-phenylethyl]-3-quinolin-5-ylguanidine) is a novel, potent, and selective antagonist radioligand for P2X7 receptors.

ATP-sensitive P2X7 receptors are localized on cells of immunological origin including peripheral macrophages and glial cells in the CNS. Activation of P2X7 receptors leads to rapid changes in intracellular calcium concentrations, release of the pro-inflammatory cytokine IL-1beta, and following prolonged agonist exposure, the formation of cytolytic pores in plasma membranes. Data from gene knockout studies and recently described selective antagonists indicate a role for P2X7 receptor activation in inflammation and pain.