Preclinical Pharmacology of ABT-594: A Nicotinic Acetylcholine Receptor Agonist for the Treatment of Pain

ABT-594 [(R)-5-(2-azetedinylmethoxy)-2-chloropyridine mono-tosylate salt] is a neuronal nicotinic acetylcholine receptor (nAChR) agonist with antinociceptive activity in rodent pain models. Whereas the binding affinity of ABT-594 at α₄β₂-containing nAChRs is comparable to that of (±)-epibatidine, ABT-594 has lower affinity than (±)-epibatidine at α₃-containing nAChRs. Similarly, ABT-594 is approximately equivalent to (±)-epibatidine in a Ca²⁺ flux assay in K-177 cells that express 04132 nAChRs but less potent than (±)-epibatidine in the IMR-32 (α₃-containing) cell line. ABT-594 is active in a variety of rodent models of acute thermal (mouse hot-plate, rat thermal paw withdrawal), persistent chemical (mouse abdominal constriction, rat formalin) and neuropathic (diabetic neuropathy and Chung spinal nerve ligation in rats) pain. Effects of ABT-594 on acute thermal pain appear to be mediated centrally and may involve activation of descending inhibition originating in the brainstem. ABT-594 decreases responses of wide dynamic range neurons in the dorsal lumbar spinal cord to noxious thermal and mechanical stimuli but does not alter responses of these neurons to innocuous stimuli. ABT-594 has plasma elimination half life ranging from < 0.5 h in mice to 4.7 h in dogs and readily penetrates the CNS. Oral bioavailability ranges from 35 to 80% in a variety of species. In rats, the majority of ABT-594 is excreted in the urine after both oral and intravenous administration, and parent drug accounts for better than 75% of total radioactivity in plasma after administration of labeled ABT-594 (AUC_0–12)