Medicinal Chemistry Research

, Volume 21, Issue 12, pp 4395–4402 | Cite as

Synthesis and evaluation of some new 4-aminopyridine derivatives as a potent antiamnesic and cognition enhancing drugs

Original Research

Abstract

4-Aminopyridine (4AP) potentiates acetylcholine (ACh) release by blocking potassium channel in axon terminal and can be used in the treatment of Alzheimer’s type of dementia and cognitive disorder. It is reported that ACh is well related with memory and learning. On the basis of these fact, we decided to synthesis and evaluate some new Schiff bases of 4AP (SBAPs) for their putative cognition enhancing, antiamnesic, and anticholinesterase activity. The synthesized and purified SBAPs were characterized by elemental analysis, UV, FTIR, 1H-, and 13C-NMR. SBAPs facilitated the learning on elevated plus maze model and they also significantly reversed the scopolamine-induced amnesia on the same model. The effect of SBAPs on learning and memory was qualitatively similar to standard nootropic drug piracetam used. The SBAPs were found to inhibit acetylcholinesterase enzyme significantly in specific brain regions prefrontal cortex, hippocampus, and hypothalamus. Thus, SBAPs derivatives showed cognitive and antiamnesic activities in the model tested and these effects may probably be due to their anticholinesterase activity.

Keywords

4-Aminopyridine Nootropic Antiamnesic Anticholinesterase Elevated plus maze 

Notes

Acknowledgment

The authors gratefully acknowledge the University Grants Commission (UGC), New Delhi, India for the financial support to Mr. Saurabh K. Sinha (Grant no. R/Dev./IX-Sch./(SRF-JRF) Pharm./15402).

References

  1. Andreani A, Leoni A, Locatelli A, Morigi R, Rambaldi M, Pietra C, Villetti G (2000) 4-Aminopyridine derivatives with antiamnesic activity. Eur J Med Chem 35:77–82CrossRefPubMedGoogle Scholar
  2. Bartus RT, Dean RL, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414CrossRefPubMedGoogle Scholar
  3. Belluti F, Piazzi L, Bisi A, Gobbi S, Bartolini M, Cavalli A, Valenti P, Rampa A (2009) Design, synthesis and evaluation of benzophenone derivatives as novel acetylcholinesterase inhibitors. Eur J Med Chem 44:1341–1348CrossRefPubMedGoogle Scholar
  4. Belluti F, Bartolini M, Bottegoni G, Bisi A, Cavalli A, Andrisano V, Rampa A (2011) Benzophenone-based derivatives: a novel series of potent and selective dual inhibitors of acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation. Eur J Med Chem 46:1682–1693CrossRefPubMedGoogle Scholar
  5. Cavallito CJ, Yun HS, Edwards ML, Foldes FF (1971) Choline acetyltransferase inhibitors. Styrylpyridine analogs with nitrogen-atom modifications. J Med Chem 14:130–133CrossRefPubMedGoogle Scholar
  6. Davies P, Maloney AJ (1976) Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 25:1403CrossRefGoogle Scholar
  7. Dhingra D, Parle M, Kulkarni SK (2004) Memory enhancing activity of glycyrrhiza glabra in mice. J Ethnopharmacol 91:361–365CrossRefPubMedGoogle Scholar
  8. Ellman GL, Courtney KD, Andres V Jr, Feather-Stone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95CrossRefPubMedGoogle Scholar
  9. Folgering H, Rutten J, Agoston S (1979) Stimulation of phrenic nerve activity by an acetylcholine releasing drug: 4-Aminopyridine. Pflugers Arch 379:181–185CrossRefPubMedGoogle Scholar
  10. Galisteo M, Rissel M, Sergent O, Chevanne M, Cillard J, Guillouzo A, Lagadic-Gossmann D (2000) Hepatotoxicity of tacrine: occurrence of membrane fluidity alterations without involvement of lipid peroxidation. J Pharmacol Exp Ther 294:160–167PubMedGoogle Scholar
  11. Giacobini E (2001) Is anti-cholinesterase therapy of Alzheimer’s disease delaying progression? Aging (Milano) 13:247–254Google Scholar
  12. Giovannini MG, Casamenti F, Bartolini L, Pepeu G (1997) The brain cholinergic system as a target of cognition enhancers. Behav Brain Res 83:1–5CrossRefPubMedGoogle Scholar
  13. Glover WE (1982) The aminopyridines. Gen Pharmacal 13:259–285CrossRefGoogle Scholar
  14. Glowinski J, Iversen LL (1966) Regional studies of catecholamines in the rat brain. I. The disposition of [3H] norepinephrine, [3H] dopamine and [3H] dopa in various regions of the brain. J Neurochem 13:655–669CrossRefPubMedGoogle Scholar
  15. Grossberg GT, Stahelin HB, Messina JC, Anand R, Veach J (2000) Lack of adverse pharmacodynamic drug interactions with rivastigmine and twenty-two classes of medications. Int J Geriatr Psychiatry 15:242–247CrossRefPubMedGoogle Scholar
  16. Gualtieri F, Manetti D, Romanelli MN, Ghelardini C (2002) Design and study of piracetam-like nootropics, controversial members of the problematic class of cognition-enhancing drugs. Curr Pharm Des 8:125–138CrossRefPubMedGoogle Scholar
  17. Hakansson L (2009) Mechanism of action of cholinesterase inhibitors in Alzheimer’s disease. Acta Neurol Scand 88:7–9CrossRefGoogle Scholar
  18. Harley CW, Lacaille JC, Galway M (1983) Hypothalamic afferents to the dorsal dentate gyrus contain acetylcholinesterase. Brain Res 270:335–339CrossRefPubMedGoogle Scholar
  19. Itoh J, Nabeshima T, Kameyama T (1990) Utility of an elevated plus maze for the evaluation of memory in mice: Effects of nootropics, scopolamine and electroconvulsive shock. Psychopharmacology (Berl) 101:27–33CrossRefGoogle Scholar
  20. Knowlton BJ, Fanselow MS (1998) The hippocampus, consolidation and online memory. Curr Opin Neurobiol 8:293–296CrossRefPubMedGoogle Scholar
  21. Kumar V, Singh PN, Bhattacharya SK (2000) Effect of Indian Hypericum perforatum Linn on animal models of cognitive dysfunction. J Ethnopharmacol 72:119–128CrossRefPubMedGoogle Scholar
  22. Lahiri DK, Farlow MR, Greig NH, Sambamurti K (2002) Current drug targets for Alzheimer’s disease treatment. Drug Dev Res 56:267–281CrossRefGoogle Scholar
  23. Lowry OH, Rosebrough NJ, Farr AL, Rendall RJ (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  24. Milner PM (1991) Brain-stimulation reward: a review. Can J Psychol 45:1–36CrossRefPubMedGoogle Scholar
  25. Murray NMF, Newsome-Davis J (1981) Treatment with oral 4-aminopyridine in disorders of neuromuscular transmission. Neurology 31:265–271CrossRefPubMedGoogle Scholar
  26. Pandey S, Srivastava RS (2010) Synthesis and characterization of some heterocyclic Schiff bases: potential anticonvulsant agents. Med Chem Res 20:1091–1101CrossRefGoogle Scholar
  27. Perry EK, Gibson PH, Blessed G, Perry RH, Tomlinson BE (1977) Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue. J Neurol Sci 34:247–265CrossRefPubMedGoogle Scholar
  28. Polman CH, Bertelsmann FW, van Loenen AC, Koeteier JC (1994) 4-aminopyridine in the treatment of patients with multiple sclerosis. Arch Neurol 51:292–296CrossRefPubMedGoogle Scholar
  29. Rakesh Ojha, Alakh NS, Muruganandam AV, Gireesh KS, Sairam K (2010) Asparagus recemosus enhances memory and protects against amnesia in rodent models. Brain Cogn 74:1–9CrossRefGoogle Scholar
  30. Scipione L, De Vita D, Musella A, Flammini L, Bertoni S, Barocelli E (2008) 4-Aminopyridine derivatives with anticholinesterase and antiamnesic activity. Bioorg Med Chem Lett 18:309–312CrossRefPubMedGoogle Scholar
  31. Sharma AC, Kulkarni SK (1992) Evaluation of learning and memory mechanisms employing elevated plus-maze in rats and mice. Prog Neuropsychopharmacol Biol Psychiatry 16:117–125CrossRefPubMedGoogle Scholar
  32. Singh GK, Garabadu D, Muruganandam AV, Joshi VK, Krishnamurthy S (2009) Antidepressant activity of Asparagus recemosus in rodent models. Pharmacol Biochem Behav 91:283–290CrossRefPubMedGoogle Scholar
  33. Solari A, Uitdehaag BMJ, Giuliani G, Pucci E, Taus C (2001) Aminopyridines for symptomatic treatment in multiple sclerosis. Cochrane Database Syst Rev (4): CD001330Google Scholar
  34. Soriano-Mas C, Redolar-Ripoll D, Aldavert-Vera L, Morgado-Bernal I, Segura-Torres P (2005) Post-training intracranial self-stimulation facilitates a hippocampus-dependent task. Behav Brain Res 160:141–147CrossRefPubMedGoogle Scholar
  35. Squire LR, Zola-Morgan S (1991) The medial temporal lobe memory system. Science 253:1380–1386CrossRefPubMedGoogle Scholar
  36. Stork CM, Hoffman RS (1994) Characterization of 4-aminopyradine in overdose. J Toxicol Clin Toxicol 32:583–587CrossRefPubMedGoogle Scholar
  37. Taylor P (2001) Anticholinesterase agents. In: Hardman JG, Limbird LE (eds) The pharmacological basis of therapeutics, 10th edn. McGraw-Hill, New York, p 175Google Scholar
  38. Tronel S, Matthijs GPF, Susan JS (2004) Noradrenergic action in prefrontal cortex in the late stage of memory consolidation. Learn Mem 11:453–458CrossRefPubMedGoogle Scholar
  39. Yamada N, Hattori A, Hayashi T, Nishikawa T, Fukuda H, Fujino T (2004) Improvement of scopolamine-induced memory impairment by Z-ajoene in the water maze in mice. Pharmacol Biochem Behav 78:787–791CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutics, Institute of TechnologyBanaras Hindu UniversityVaranasiIndia
  2. 2.Research and Development CentreVaranasiIndia

Personalised recommendations