Skip to main content
PMC home page
CNS Drug Reviews logoLink to CNS Drug Reviews
. 2006 Jun 7;10(2):167–182. doi: 10.1111/j.1527-3458.2004.tb00011.x

ABT‐089: Pharmacological Properties of a Neuronal Nicotinic Acetylcholine Receptor Agonist for the Potential Treatment of Cognitive Disorders

Lynne E Rueter 1,✉, David J Anderson 1, Clark A Briggs 1, Diana L Donnelly‐Roberts 1, Gary A Gintant 1, Murali Gopalakrishnan 1, Nan‐Horng Lin 1, Mark A Osinski 1, Glenn A Reinhart 1, Michael J Buckley 1, Ruth L Martin 1, Jeffrey S McDermott 1, Lee C Preusser 1, Terese R Seifert 1, Zhi Su 1, Bryan F Cox 1, Michael W Decker 1, James P Sullivan 1
PMCID: PMC6741767  PMID: 15179445

ABSTRACT

ABT‐089 [2‐methyl‐3‐(2‐(S)‐pyrrolidinylmethoxy)pyridine dihydrochloride salt] is a selective neuronal nicotinic receptor (NNR) modulator with cognitive enhancing properties in animal models of cognitive functioning. Amongst NNR subtypes, ABT‐089 shows selectivity for the cytisine binding site on the α4β2 receptor subtype as compared to the α‐bungarotoxin (α‐BgT) binding sites on the α7 and α1β1δγ receptor subtypes. In functional in vitro electrophysiological and cation flux assays, ABT‐089 displays differential activity including agonism, partial agonism and antagonism depending upon the NNR subtype and assay. ABT‐089 is as potent and efficacious as (–)‐nicotine at evoking acetylcholine (ACh) release from hippocampal synaptosomes. Furthermore, ABT‐089 is neuroprotective against excitotoxic glutamate insults, with even greater potency seen after chronic treatment. Similarly, ABT‐089 is effective in models of cognitive functioning, including enhancement of baseline functioning as well as improvement of impaired cognitive functioning seen following septal lesioning and natural aging. In neuroprotective assays the compound is most potent by chronic administration. In stark contrast to the positive effects in the cognitive models, ABT‐089 shows little propensity to induce adverse

Keywords: ABT‐089, Alzheimer's disease, Attention deficit disorder, Cognitive disorders, Neuronal nicotinic acetylcholine receptor

Full Text

The Full Text of this article is available as a PDF (150.2 KB).

REFERENCES

  • 1. Arneric SP, Bannon AW, Brioni JD, et al. ABT‐089: an orally effective cholinergic channel modulator (ChCM) with cognitive enhancement and neuroprotective action In: Becker R. and Giacobini E, Eds. Alzheimer Disease: From Molecular Biology to Therapy. Boston : Birkhäuser, 1996;287–291. [Google Scholar]
  • 2. Ashworth‐Preece M, Jarrott B, Lawrence AJ. Nicotinic acetylcholine receptors in the rat and primate nucleus tractus solitarius and on rat and human inferior vagal (nodose) ganglia: Evidence from in vivo microdialysis and [125I] α‐bungarotoxin autoradiography. Neuroscience 1998;83:1113–1122. [DOI] [PubMed] [Google Scholar]
  • 3. Beani L, Antonelli T, Tomasini MC, Marani L, Bianchi C. The nicotinic modulation of [H‐3]D‐aspartate outflow in primary cultures of rat neocortical neurons: Effect of acute and long term nicotine treatment. Neuropharmacology 2000;39:2646–2653. [DOI] [PubMed] [Google Scholar]
  • 4. Bertrand D., Devillers‐Thiéry A, Revah F, et al. Unconventional pharmacology of a neuronal nicotinic receptor mutated in the channel domain. Proc Natl Acad Sci USA 1992;89:1261–1265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Bertrand D, Galzi J‐L, Devillers‐Thiéry A, Bertrand S, Changeux J‐P. Mutations at two distinct sites within the channel domain M2 alter calcium permeability of neuronal α7 nicotinic receptor. Proc Natl Acad Sci USA 1993;90:6971–6975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. Briggs CA, McKenna DG. Activation and inhibition of the human α7 nicotinic acetylcholine receptor by agonists. Neuropharmacology 1998;37:1095–1102. [DOI] [PubMed] [Google Scholar]
  • 7. Briggs CA, McKenna DG, Monteggia LM, et al. Gain of function mutation of the α7 nicotinic acetylcholine receptor: Distinct pharmacology of the human α7V274T variant. Eur J Pharmacol 1999;366:301–308. [DOI] [PubMed] [Google Scholar]
  • 8. Buccafusco JJ, Jackson WJ. Beneficial effects of nicotine administered prior to a delayed matching‐to‐sample task in young and aged monkeys. Neurobiol Aging 1991;12:233–238. [DOI] [PubMed] [Google Scholar]
  • 9. Cordero‐Erausquin M, Marubio LM, Klink R, Changeux J‐P. Nicotinic receptor function: New perspectives from knockout mice. Trends Pharmacol Sci 2000;21:211–217. [DOI] [PubMed] [Google Scholar]
  • 10. Decker MW, Bannon AW, Curzon P, et al. ABT‐089 [2‐methyl‐3‐(2‐(S)‐pyrrolidinylmethoxy)pyridine dihydrochloride]: II. A novel cholinergic channel modulator with effects on cognitive performance in rats and monkeys. J Pharmacol Exp Ther 1997;283:247–258. [PubMed] [Google Scholar]
  • 11. Decker MW, Majchrzak MJ, Arneric SP. Effects of lobeline, a nicotinic receptor agonist, on learning and memory. Pharmacol Biochem Behav 1993;45:571–576. [DOI] [PubMed] [Google Scholar]
  • 12. Donnelly‐Roberts DL, Brioni JD. Preclinical evidence on the neuroprotective effects of nicotinic ligands In: Arneric SP, Brioni JD, Eds. Neuronal Nicotinic Receptors: Pharmacology and Therapeutic Opportunities. Indianapolis : Wiley‐Liss, Inc., 1999:337–348. [Google Scholar]
  • 13. Donnelly‐Roberts DL, Xue IC, Arneric SP, Sullivan JP. In vitro neuroprotective properties of the novel cholinergic channel activator (ChCA), ABT‐418. Brain Res 1996;719:36–44. [DOI] [PubMed] [Google Scholar]
  • 14. Ferris SH. Evaluation of memantine for the treatment of Alzheimer's disease. Expert Opin Pharmacother 2003;4:2305–2313. [DOI] [PubMed] [Google Scholar]
  • 15. Fu Y, Matta SG, Sharp BM. Local α‐bungarotoxin‐sensitive nicotinic receptors modulate hippocampal norepinephrine release by systemic nicotine. J Pharmacol Exp Ther 1999;289:133–139. [PubMed] [Google Scholar]
  • 16. Fucile S, Renzi M, Lax P, Eusebi F. Fractional Ca2+ current through human neuronal alpha 7 nicotinic acetyl‐choline receptors. Cell Calcium 2003;34:205–209. [DOI] [PubMed] [Google Scholar]
  • 17. Girod R, Barazangi N, McGehee DS, Role LW. Facilitation of glutamatergic neurotransmission by presynaptic nicotinic acetylcholine receptors. Neuropharmacology 2000;39:2715–2725. [DOI] [PubMed] [Google Scholar]
  • 18. Haass M, Kubler W. Nicotine and sympathetic neurotransmission. Cardiovasc Drugs Ther 1997. 10:657–65. [DOI] [PubMed] [Google Scholar]
  • 19. Kaiser S, Wonnacott S. alpha‐Bungarotoxin‐sensitive nicotinic receptors indirectly modulate [H–3]dopamine release in rat striatal slices via glutamate release. Mol Pharmacol 2000;58:312–318. [DOI] [PubMed] [Google Scholar]
  • 20. Karlin A, Akabas MH. Toward a structural basis for the function of nicotinic acetylcholine receptors and their cousins. Neuron 1995;15:1231–1244. [DOI] [PubMed] [Google Scholar]
  • 21. Kofalvi A, Sperlagh B, Zelles T, Vizi ES. Long‐lasting facilitation of 4‐amino‐n‐[2,3‐H‐3]butyric acid ([H‐3]GABA) release from rat hippocampal slices by nicotinic receptor activation. J Pharmacol Exp Ther 2000;295:453–462. [PubMed] [Google Scholar]
  • 22. Levin ED. Nicotinic receptor subtypes and cognitive function. J Neurobiol 2002;53:633–640. [DOI] [PubMed] [Google Scholar]
  • 23. Li X, Rainnie DG, McCarley RW, Greene RW. Presynaptic nicotinic receptors facilitate monoaminergic transmission. J Neurosci 1998;18:1904–1912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Liang SD, Vizi ES. Positive feedback modulation of acetylcholine release from isolated rat superior cervical ganglion. J Pharmacol Exp Ther 1997;280:650–655. [PubMed] [Google Scholar]
  • 25. Lin N‐H, Gunn DE, Ryther KB, et al. Structure‐activity studies on 2‐methyl‐3‐(2(S)‐pyrrolidinylmethoxy)pyridine (ABT‐089): An orally bioavailable 3‐pyridyl ether nicotinc acetylcholine receptor ligand with cognition‐enhancing properties. J Med Chem 1997;40:385–390. [DOI] [PubMed] [Google Scholar]
  • 26. Lipton SA, Rosenberg, PA . Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 1994;330:934–940. [DOI] [PubMed] [Google Scholar]
  • 27. Lukas RJ. Characterization of curaremimetic neurotoxin binding sites on membrane fractions derived from the human neuroblastoma clonal line TE 671. J Neurochem 1986;45:1936–1941. [DOI] [PubMed] [Google Scholar]
  • 28. Lukas RJ. Expression of ganglia‐type nicotinic acetylcholine receptors and nicotinic ligand binding sites by cells of the IMR‐32 human neuroblastoma clonal line. J Pharmacol Exp Ther 1993;265:294–302. [PubMed] [Google Scholar]
  • 29. Marchi M, Risso F, Viola C, Cavazzani P, Raiteri M. Direct evidence that release‐stimulating alpha 7* nicotinic cholinergic receptors are localized on human and rat brain glutamatergic axon terminals. J Neurochem 2002;80:1071–1078. [DOI] [PubMed] [Google Scholar]
  • 30. Marks MJ, Burch JB, Collins AC. Genetics of nicotine response in four inbred strains of mice. J Pharmacol Exp Ther 1983;226:291–302. [PubMed] [Google Scholar]
  • 31. Marks MJ, Farnham DA, Grady SR, Collins AC. Nicotinic receptor function determined by stimulation of rubidium efflux from mouse brain synaptosomes. J Pharmacol Exp Ther 1993;264:542–552. [PubMed] [Google Scholar]
  • 32. Newhouse PA, Kelton M. Nicotinic systems in central nervous systems disease: Degenerative disorders and beyond. Pharm Acta Helv 2000;74:91–101. [DOI] [PubMed] [Google Scholar]
  • 33. Papke RL, Porter Papke JK Comparative pharmacology of rat and human alpha 7 nAChR conducted with net charge analysis. Br J Pharmacol 2002;137:49–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Prendergast MA, Jackson WJ, Terry AV Jr, Decker MW, Arneric SP, Buccafusco JJ. Central nicotinic receptor agonists ABT‐418, ABT‐089, and (–) nicotine reduce distractability in adult monkeys. Psychopharmacology 1998;136:50–58. [DOI] [PubMed] [Google Scholar]
  • 35. Roch J‐M, Puttfarcken PS. Biological actions of the β‐amyloid protein and its precursor. Curr Drugs 1996;1:9–16. [Google Scholar]
  • 36. Sands SB, Costa ACS, Patrick JW. Barium permeability of neuronal nicotinic receptor α7 expressed in Xenopus oocytes. Biophys J 1993;65:2614–2621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Séguéla P, Wadiche J, Dineley‐Miller K, Dani JA, Patrick JW. Molecular cloning, functional properties, and distribution of rat brain α7: A nicotinic cation channel highly permeable to calcium. J Neurosci 1993;13:596–604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Skok VI. Nicotinic acetylcholine receptors in autonomic ganglia. Auton Neurosci 2002;18:1–11. [DOI] [PubMed] [Google Scholar]
  • 39. Spencer TJ, Biederman J, Wilens TE, Faraone SV. Novel treatments for attention‐deficit/hyperactivity disorders in children. J Clin Psychiatry 2002;63(Suppl 12):16–22. [PubMed] [Google Scholar]
  • 40. Sullivan JP, Donnelly‐Roberts D, Briggs CA, et al. ABT‐089 [2‐methyl‐3‐(2‐(S)‐pyrrolidinylmethoxy)pyri‐dine]: I. A potent and selective cholinergic channel modulator with neuroprotective properties. J Pharmacol Exp Ther 1997;283:235–246. [PubMed] [Google Scholar]
  • 41. Tucci SA, Genn RF, File SE. Methyllycaconitine (MLA) blocks the nicotine evoked anxiogenic effect and 5‐HT release in the dorsal hippocampus: Possible role of alpha 7 receptors. Neuropharmacology 2003;44:367–373. [DOI] [PubMed] [Google Scholar]
  • 42. Wernicke JF, Kratochvil CJ. Safety profile of atomoxetine in the treatment of children and adolescents with ADHD. J Clin Psychiatry 2002;63(Suppl 12):50–55. [PubMed] [Google Scholar]
  • 43. Yamada K, Toshitaka N. Therapeutic approaches to the treatment of Alzheimer's disease. Drugs Today 2002;38:631–637. [DOI] [PubMed] [Google Scholar]

Articles from CNS Drug Reviews are provided here courtesy of Wiley

RESOURCES