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Donnelly-Roberts DL, Puttfarcken PS, Kuntzweiler TA, Briggs CA, Anderson DJ, Campbell JE, Piattoni-Kaplan M, McKenna DG, Wasicak JT, Holladay MW, Williams M, Arneric SP. 
“ABT-594 [R-5-2-azetidinylmethoxy-2-chloropyridine]: a novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: IIn vitro characterization”. 
J Pharmacol Exp Ther. 1998 May 08;285(2):777-86.
The discovery of +/--epibatidine, a naturally occurring neuronal nicotinic acetylcholine receptor nAChR agonist with antinociceptive activity 200-fold more potent than that of morphine, has renewed interest in the potential role of nAChRs in pain processing. However, +/--epibatidine has significant side-effect liabilities associated with potent activity at the ganglionic and neuromuscular junction nAChR subtypes which limit its potential as a clinical entity. ABT-594 [R-5-2-azetidinylmethoxy-2-chloropyridine] is a novel, potent cholinergic nAChR ligand with analgesic properties see accompanying paper by Bannon et al., 1998b that shows preferential selectivity for neuronal nAChRs and a consequently improved in vivo side-effect profile compared with +/--epibatidine. ABT-594 is a potent inhibitor of the binding of [3H]--cytisine to alpha 4 beta 2 neuronal nAChRs Ki = 37 pM, rat brain Ki = 55 pM, transfected human receptor. At the alpha 1 beta 1 delta gamma neuromuscular nAChR labeled by [125I] alpha-bungarotoxin alpha-Btx, ABT-594 has a Ki value of 10,000 nM resulting in a greater than 180,000-fold selectivity of the compound for the neuronal alpha 4 beta 2 nAChR. In contrast, +/--epibatidine has Ki values of 70 pM and 2.7 nM at the alpha 4 beta 2 and alpha 1 beta 1 delta gamma nAChRs, respectively, giving a selectivity of only 38-fold. The S-enantiomer of ABT-594, A-98593 has activity at the neuronal alpha 4 beta 2 nAChR identical with ABT-594 Ki = 34-39 pM, which demonstrates a lack of stereospecific binding similar to that reported previously for +/--epibatidine. A similar lack of stereoselectivity is seen at the human alpha 7 receptor. However, A-98593 is 3-fold more potent at the neuromuscular nAChR Ki = 3420 nM and the brain alpha-Btx-sensitive nAChR Ki = 4620 nM than ABT-594. ABT-594 has weak affinity in binding assays for adrenoreceptor subtypes alpha-1B Ki = 890 nM, alpha-2B Ki = 597 nM and alpha-2C Ki = 342 nM, and it has negligible affinity Ki > 1000 nM for approximately 70 other receptors, enzyme and transporter binding sites. Functionally, ABT-594 is an agonist. At the transfected human alpha 4 beta 2 neuronal nAChR K177 cells, with increased 86Rb+ efflux as a measure of cation efflux, ABT-594 had an EC50 value of 140 nM with an intrinsic activity IA compared with --nicotine of 130 at the nAChR subtype expressed in IMR-32 cells sympathetic ganglion-like, an EC50 of 340 nM IA = 126 at the F11 dorsal root ganglion cell line sensory ganglion-like, an EC50 of 1220 nM IA = 71 and via direct measurement of ion currents, an EC50 value of 56,000 nM IA = 83 at the human alpha 7 homooligimeric nAChR produced in oocytes. A-98593 is 2- to 3-fold more potent and displays approximately 50 greater intrinsic activity than ABT-594 in all four functional assays. In terms of potency, ABT-594 is 8- to 64-fold less active than +/--epibatidine and also has less IA in these functional assays. ABT-594 30 microM inhibits the release of calcitonin gene-related peptide from C-fibers terminating in the dorsal horn of the spinal cord, an effect mediated via nAChRs. Pharmacologically, ABT-594 has an in vitro profile distinct from that of the prototypic nicotinic analgesic +/--epibatidine, with the potential for substantially reduced side-effect liability and, as such, represents a potentially novel therapeutic approach to pain management.
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