P2X Receptor Antagonists - P2X receptors are a family of ATP-gated non-selective ion channels of which seven P2X subunits (P2Xi.7) have been cloned (71). ATP is the endogenous ligand and produces intense pain when injected intradermal^ (72). Adenine nucleotide derivatives such as oxidized ATP and TNP-ATP have been reported to possess some P2X sub-type specificity and to produce antinociceptive effects in animal pain models (73,74). Although non-selective, P2 receptor antagonists such as suramin and PPADS were shown to produce antinociceptive responses in neuropathic pain models (71,72,75). The structurally novel, non-nucleotide P2X3- and P2X2/3-antagonist (K, = 22-92 nM) A-317491 (29) was reported to reverse CCI-induced mechanical and thermal hypersensitivity with ED50 values between 10 and 15 ng/kg s.c (76). The effects were stereospecific, as the corresponding R-enantiomer (A-317344) was inactive.
Nicotine Receptor Modulators - Activation of neuronal nicotinic acetylcholine receptors (nACHR) has been associated with analgesic effects in neuropathic pain models (77). The a4p2-selective nACHR agonist ABT-594 (30) had antinociceptive effects in animal pain models with a reduced side-effect profile compared to nicotine (35). Pyridinyl derivative TC-2403 (31) represents another potent a4p2-selective
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