Pozanicline Explained

Pozanicline (INN,[1] codenamed ABT-089) is a drug developed by Abbott, that has nootropic and neuroprotective effects.[2] [3] [4] Animal studies suggested it useful for the treatment of ADHD[5] and subsequent human trials have shown ABT-089 to be effective for this application.[6] It binds with high affinity subtype-selective to the α4β2 nicotinic acetylcholine receptors and has partial agonism to the α6β2 subtype,[7] [8] but not the α7 and α3β4 subtypes familiar to nicotine. It has particularly low tendency to cause side effects compared to other drugs in the class.[9] [10]

Synthesis

Pozanicline is synthesized from 2-methyl-3-hydroxypyridine and Boc-L-Prolinol through a dehydration reaction followed by deprotection of the nitrogen atom of prolinol[11]

Notes and References

  1. Web site: International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 62 . World Health Organization . 3 January 2017 . 257 . live . https://web.archive.org/web/20160518204538/http://www.who.int/medicines/publications/druginformation/innlists/RL62.pdf . 18 May 2016 .
  2. Lin NH, Gunn DE, Ryther KB, Garvey DS, Donnelly-Roberts DL, Decker MW, Brioni JD, Buckley MJ, Rodrigues AD, Marsh KG, Anderson DJ, Buccafusco JJ, Prendergast MA, Sullivan JP, Williams M, Arneric SP, Holladay MW . 6 . Structure-activity studies on 2-methyl-3-(2(S)-pyrrolidinylmethoxy) pyridine (ABT-089): an orally bioavailable 3-pyridyl ether nicotinic acetylcholine receptor ligand with cognition-enhancing properties . Journal of Medicinal Chemistry . 40 . 3 . 385–90 . January 1997 . 9022806 . 10.1021/jm960233u .
  3. Sullivan JP, Donnelly-Roberts D, Briggs CA, Anderson DJ, Gopalakrishnan M, Xue IC, Piattoni-Kaplan M, Molinari E, Campbell JE, McKenna DG, Gunn DE, Lin NH, Ryther KB, He Y, Holladay MW, Wonnacott S, Williams M, Arneric SP . 6 . ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine]: I. A potent and selective cholinergic channel modulator with neuroprotective properties . The Journal of Pharmacology and Experimental Therapeutics . 283 . 1 . 235–46 . October 1997 . 9336329 .
  4. Decker MW, Bannon AW, Curzon P, Gunther KL, Brioni JD, Holladay MW, Lin NH, Li Y, Daanen JF, Buccafusco JJ, Prendergast MA, Jackson WJ, Arneric SP . 6 . 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 . The Journal of Pharmacology and Experimental Therapeutics . 283 . 1 . 247–58 . October 1997 . 9336330 .
  5. Prendergast MA, Jackson WJ, Terry AV, Decker MW, Arneric SP, Buccafusco JJ . Central nicotinic receptor agonists ABT-418, ABT-089, and (-)-nicotine reduce distractibility in adult monkeys . Psychopharmacology . 136 . 1 . 50–8 . March 1998 . 9537682 . 10.1007/s002130050538 . 20080069 .
  6. Wilens TE, Verlinden MH, Adler LA, Wozniak PJ, West SA . 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 . 1065–70 . June 2006 . 16499880 . 10.1016/j.biopsych.2005.10.029 . 24951969 .
  7. Marks MJ, Wageman CR, Grady SR, Gopalakrishnan M, Briggs CA . Selectivity of ABT-089 for alpha4beta2* and alpha6beta2* nicotinic acetylcholine receptors in brain . Biochemical Pharmacology . 78 . 7 . 795–802 . October 2009 . 19481067 . 2772152 . 10.1016/j.bcp.2009.05.022 .
  8. Anderson DJ, Malysz J, Grønlien JH, El Kouhen R, Håkerud M, Wetterstrand C, Briggs CA, Gopalakrishnan M . 6 . Stimulation of dopamine release by nicotinic acetylcholine receptor ligands in rat brain slices correlates with the profile of high, but not low, sensitivity alpha4beta2 subunit combination . Biochemical Pharmacology . 78 . 7 . 844–51 . October 2009 . 19555668 . 10.1016/j.bcp.2009.06.024 .
  9. Rueter LE, Anderson DJ, Briggs CA, Donnelly-Roberts DL, Gintant GA, Gopalakrishnan M, Lin NH, Osinski MA, Reinhart GA, Buckley MJ, Martin RL, McDermott JS, Preusser LC, Seifert TR, Su Z, Cox BF, Decker MW, Sullivan JP . 6 . ABT-089: pharmacological properties of a neuronal nicotinic acetylcholine receptor agonist for the potential treatment of cognitive disorders . CNS Drug Reviews . 10 . 2 . 167–82 . 2004 . 15179445 . 6741767 . 10.1111/j.1527-3458.2004.tb00011.x .
  10. Wilens TE, Decker MW . Neuronal nicotinic receptor agonists for the treatment of attention-deficit/hyperactivity disorder: focus on cognition . Biochemical Pharmacology . 74 . 8 . 1212–23 . October 2007 . 17689498 . 2974320 . 10.1016/j.bcp.2007.07.002 .
  11. Rueter LE, Anderson DJ, Briggs CA, Donnelly-Roberts DL, Gintant GA, Gopalakrishnan M, Lin NH, Osinski MA, Reinhart GA, Buckley MJ, Martin RL, McDermott JS, Preusser LC, Seifert TR, Su Z, Cox BF, Decker MW, Sullivan JP . 6 . ABT-089: pharmacological properties of a neuronal nicotinic acetylcholine receptor agonist for the potential treatment of cognitive disorders . CNS Drug Reviews . 10 . 2 . 167–82 . 2006 . 15179445 . 6741767 . 10.1111/j.1527-3458.2004.tb00011.x .

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