Poison Arrow Frogs and Abbott Labs (14)
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The seventeen nAChRs are agonized by several pharmaceutical compounds, most of which are not FDA approved for the treatment of any condition.
Epibatidine is a chlorinated alkaloid secreted by the Ecuadoran amphibian Epipedobates anthonyi, also known as Anthony’s poison arrow frog – a misnomer, as it was never used for poison arrows. The alkaloid was discovered by the world authority on amphibian alkaloids, National Institutes of Health researcher John W. Daly (elected to the National Academy of Sciences in 1997) in 1974. Epibatidine, found on the skin of the frog, binds to both nicotinic and muscarinic receptors. It causes numbness and paralysis and kills through respiratory arrest. Note that in captivity, the frogs do not produce epibatidine due to the change in their diet (it is produced from their digestion of insects).
The numbness is what initially interested researchers in epibatidine. It relieved pain in mice in a similar way to opioids, but with 200x the potency of morphine, and without causing addiction or habituation. Its pain-relieving component was found to depend on α4β2 nAChRs, though its toxic effect depended on its activity on mAChRs. Consequently, it was viewed as an inspiration for synthetic analogs with the goal of separating its nicotinic and muscarinic effects.
Four synthetic analogues of note have been produced. First, epiboxidine had 1/10th the analgesic effect of its parent compound, with less affinity at the α4β2 receptors, but the same potency at the α3β4 receptors. Due to its toxicity, research on the compound was mostly dropped in the last decade. The pharmaceutical giant Abbott Labs produced the other two analogues of note, named ABT-594 and ABT-418. ABT-594, also called tebanicline, binds to α3β4 and α4β2 receptors. Though less toxic, it was dropped from human trials due to its intolerable side effects. ABT-418, developed with the hope of using it to treat AD and ADHD, does not bind to α3β4 receptors but does bind to α4β2, α7, and serotonin’s 5-HT3 receptors, yielding attractive neuroprotective and anxiolytic effects.
Although ABT-418 is an attractive molecule, Abbot had better success with a later development. ABT-089, also called pozanicline, has a high affinity for a α4β2 receptors (like nicotine), partial agonism for α6β2 receptors, and does not agonize the α7 and α2β4 receptors. It is neuroprotective, well-tolerated and has been used to treat symptoms of ADHD.
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 Daly, J. W., Garraffo, H. M., Spande, T. F., Decker, M. W., Sullivan, J. P., & Williams, M. (2000). Alkaloids from frog skin: the discovery of epibatidine and the potential for developing novel non-opioid analgesics. Natural product reports, 17(2), 131-135.  Traynor, J. R. (1998). Epibatidine and pain. British journal of anaesthesia, 81(1), 69-76.  Kulu, I., & Ocal, N. (2011). The synthesis of epiboxidine and related analogues as potential pharmacological agents. Helvetica Chimica Acta, 94(11), 2054-2060.  Rowbotham, M. C., Duan, W. R., Thomas, J., Nothaft, W., & Backonja, M. M. (2009). A randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of ABT-594 in patients with diabetic peripheral neuropathic pain. Pain, 146(3), 245-252.  Donnelly-Roberts, D. L., Xue, I. C., Arneric, S. P., & Sullivan, J. P. (1996). In vitro neuroprotective properties of the novel cholinergic channel activator (ChCA), ABT-418. Brain research, 719(1-2), 36-44.  Brioni, J. D., O'Neill, A. B., Kim, D. J., Buckley, M. J., Decker, M. W., & Arneric, S. P. (1994). Anxiolytic-like effects of the novel cholinergic channel activator ABT-418. Journal of pharmacology and experimental therapeutics, 271(1), 353-361.  Sullivan, J. P., Donnelly-Roberts, D., Briggs, C. A., Anderson, D. J., Gopalakrishnan, M., Xue, I. C., ... & Gunn, D. E. (1997). ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy) pyridine]: I. A potent and selective cholinergic channel modulator with neuroprotective properties. Journal of Pharmacology and Experimental Therapeutics, 283(1), 235-246.  Wilens, T. E., Verlinden, M. H., Adler, L. A., Wozniak, P. J., & West, S. A. (2006). ABT-089, a neuronal nicotinic receptor partial agonist, for the treatment of attention-deficit/hyperactivity disorder in adults: results of a pilot study. Biological psychiatry, 59(11), 1065-1070.