Neurotherapeutics

, Volume 6, Issue 1, pp 4–13 | Cite as

Multifunctional receptor-directed drugs for disorders of the central nervous system

Review Article

Summary

The marked decline in FDA-approved new drug candidates in recent years suggests the possibility that the “low-hanging fruit” has been almost entirely harvested. This might be particularly applicable to drugs acting on the central nervous system. Fortunately, there are several examples extant for the utility of multifunctional drugs, compounds, or drug mixtures that act on multiple additive or synergistic targets. However, to exploit this approach may require the willingness to consider the possibility that drug targets might be addressed by molecules of rather low specificity and moderate potency. The expectation is that single target molecules with high specificity might not have access to complex interacting neural pathways, and that moderate potency could engender fewer off-target side effects. Though novel compounds might be developed by combining the active functional groups of two or more drug molecules, the approach still lends itself to high throughput screening of large chemical libraries. Multifunctional compounds might be designed with the ability to: 1) offer both palliative and disease modifying actions, 2) act on targets that produce additive or synergistic therapeutic responses, 3) simultaneously evoke a therapeutic response at the desired target and prevent an undesired response mediated by an alternate target, 4) allow one component to promote the drugable characteristics (e.g., brain penetration) of the therapeutic component, and 5) prolong the duration of effectiveness of one compound by contributing the pharmacodynamic actions of another. The author takes the liberty to include examples of the situations just mentioned from studies in his laboratory in the following discussion.

Key Words

Drug discovery Alzheimer’s disease cognition working memory attention deficit disorder delayed responses tasks neuroprotection 

References

  1. 1.
    Israili ZH, Hernández-Hernández R, Valasco M. The future of antihypertensive treatment. Am J Ther 2007;14:121–134.CrossRefPubMedGoogle Scholar
  2. 2.
    Korczyn AD, Nussbaum M. Emerging therapies in the pharmacological treatment ofParkinson’s disease. Drugs 2002;62:775–786.CrossRefPubMedGoogle Scholar
  3. 3.
    Jürgen Drews Case histories, magic bullets and the state of drug discovery. Nature Rev Drug Discovery 2006;5:635–640.Google Scholar
  4. 4.
    Kuroki T, Nagao N, Nakahara T. Neuropharmacology of second-generation antipsychotic drugs: a validity of the serotonin-dopamine hypothesis. Prog Brain Res 2008;172:199–212.CrossRefPubMedGoogle Scholar
  5. 5.
    Sivachenko A, Kalinin A, Yuryev A. Pathway analysis for design of promiscuous drugs and selective drug mixtures. Curr Drug Discov Technologies 2006;3:269–277.CrossRefGoogle Scholar
  6. 6.
    Van Groenendael JH, Markusse HM, Dijkmans BA, Breedveld FC. The effect of ranitidine on NSAID related dyspeptic symptoms with and without peptic ulcer disease of patients with rheumatoid arthritis and osteoarthritis. Clin Rheumatol 1996;15:450–456.CrossRefPubMedGoogle Scholar
  7. 7.
    Yeomans ND, Tulassay Z, Juhász L, Rácz I, Howard JM, van Rensburg CJ, Swannell AJ, Hawkey CJ. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med 1998;338:719–726.CrossRefPubMedGoogle Scholar
  8. 8.
    Davis M, Maida V, Daeninck P, Pergolizzi J. The emerging role of cannabinoid neuromodulators in symptom management. Supp Care Cancer 2007;15:63–71.CrossRefGoogle Scholar
  9. 9.
    Youdim MB, Weinstock M. Novel neuroprotective anti-Alzheimer drugs with anti-depressant activity derived from the anti-Parkinson drug, rasagiline. Mechanisms Ageing Develop 2002;123:1081–1086.CrossRefGoogle Scholar
  10. 10.
    Sagi Y, Weinstock M, Youdim MB. Attenuation of MPTP-induced dopaminergic neurotoxicity by ladostigil, a cholinesterase-monoamine oxidase inhibitor. J Neurochem 2003;86:290–297.CrossRefPubMedGoogle Scholar
  11. 11.
    Weinstock M, Poltyrev T, Bejar C, Youdim MB. Effect of ladostigil, a novel monoamine-oxidase cholinesterase inhibitor, in rat models of anxiety and depression. Psychopharmacology 2002;160:318–324.CrossRefPubMedGoogle Scholar
  12. 12.
    Buccafusco JJ, Terry AV Jr, Goren T, Blaugrun E. Potential cognitive actions of ladostigil, a novel neuroprotective agent, as assessed in old rhesus monkeys in their performance of versions of a delayed matching task. Neuroscience 2003;119:669–678.CrossRefPubMedGoogle Scholar
  13. 13.
    Van der Schyf CJ, Gal S, Geldenhuys WJ, Youdim MB. Multifunctional neuroprotective drugs targeting monoamine oxidase inhibition, iron chelation, adenosine receptors, and cholinergic and glutamatergic action for neurodegenerative diseases. Expert Opin Investig Drugs 2006;15:873–886.CrossRefPubMedGoogle Scholar
  14. 14.
    Yogev-Falach M, Bar-Am O, Amit T, Youdim MB. The multifunctional neuroprotective anti-Alzheimer/ anti-Parkinson drug ladostigil (TV3326) regulates holo-APP translation and processing. FASEB J 2006;20:2177–2179.CrossRefPubMedGoogle Scholar
  15. 15.
    Youdim MB, Amit T, Bar-Am O, Yogev-Falach M. Implications of co-morbidity for etiology and treatment of neurodegenerative diseases with multifunctional neuroprotective-neurorescue drugs; ladostigil. Neurotox Res 2006;10: 1–11.CrossRefGoogle Scholar
  16. 16.
    Rizzo S, Rivière C, Piazzi L, Bisi A, Gobbi S, Bartolini M, Andrisano V, Morroni F, Tarozzi A, Monti J-P, Rampa A. Benzofuran-based hybrid compounds for the inibition of cholinesterase activity, β amyloid aggregation, and Aβ neurotoxicity. J Med Chem 2008;51: 2883–2886.CrossRefPubMedGoogle Scholar
  17. 17.
    Buccafusco JJ, Terry AV Jr. Donepezil-induced improvement in delayed matching accuracy by young and old rhesus monkeys. J. Mol Neurosci 2004;24:85–91.CrossRefPubMedGoogle Scholar
  18. 18.
    Elrod K, Buccafusco JJ, Jackson WJ. Nicotine enhances delayed matching-to-sample performance by primates. Life Sci 1988;43:277–287.CrossRefPubMedGoogle Scholar
  19. 19.
    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.CrossRefPubMedGoogle Scholar
  20. 20.
    Buccafusco JJ, Prendergast M, Terry AV Jr, Jackson WJ. Cognitive effects of nicotinic cholinergic agonists in non-human primates. Drug Develop Res 1996;38:196–203.CrossRefGoogle Scholar
  21. 21.
    Rose JE, Westman EC, Behm FM. Nicotine/mecamylamine combination treatment for smoking cessation. Drug Develop Res 1996;38:243–256.CrossRefGoogle Scholar
  22. 22.
    Buccafusco JJ. Neuropharmacologic and behavioral actions of clonidine: interactions with central neurotransmitters. International Rev Neurobiol 1992;33:55–107.CrossRefGoogle Scholar
  23. 23.
    Buccafusco JJ. Inhibition of regional brain acetylcholine biosynthesis by clonidine in spontaneously hypertensive rats. Drug Devel Res 1984;4:627–633.CrossRefGoogle Scholar
  24. 24.
    Buccafusco JJ, Terry AV Jr, Webster SJ, Martin DM, Hohnadel EJ, Bouchard KA, Warner SE. The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant conditioning memory tasks for screening drug candidates. Psycho-pharmacology 2008;199:481–494.Google Scholar
  25. 25.
    Jackson WJ, Buccafusco JJ. Clonidine enhances delayed matching-to-sample performance by young and aged monkeys. Pharmacol Biochem Behav 1991;39:79–84.CrossRefPubMedGoogle Scholar
  26. 26.
    Dunbar GC, Inglis R, Kuchibhatla R, Sharma T, Tomlinson M, Wamsley J. Effect of ispronicline, a neuronal acetylcholine receptor partial agonist, in subjects with age associated memory impairment (AAMI). J Psychopharmacol 2007;21:171–178.CrossRefPubMedGoogle Scholar
  27. 27.
    Briggs CA, Anderson DJ, Brioni JD, et al. Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21. In vitro and in vivo. Pharmacol Biochem Behav 1997;57:231–241.CrossRefPubMedGoogle Scholar
  28. 28.
    Buccafusco JJ, Letchworth SR, Bencherif M, Lippillo PM. Long-lasting cognitive improvement with nicotinic receptor agonists: mechanisms of pharmacokinetic-pharmacodynamic discordance. Trends Pharmacological Sci 2005;26:352–360.CrossRefGoogle Scholar
  29. 29.
    Buccafusco JJ, Webster SJ, Terry AV Jr, Kille N, Blessing D. Protracted cognitive effects produced by clonidine in Macaca Nemestrina performing a delayed matching task. Psychopharmacology (Berl) 2008 Sep 11; [Epub ahead of print].Google Scholar
  30. 30.
    Powers JC, Buccafusco JJ, Starks K, inventors. Georgia Tech Research Corporation, Atlanta, GA, assignee. Pyridinium Compounds. US patent 5 714 615. February 3, 1998.Google Scholar
  31. 31.
    Powers JC, Buccafusco JJ, Starks K, inventors. Georgia Tech Research Corporation, Atlanta, GA, assignee. Pyridinium Compounds. US patent 5 726 314. March 10, 1998.Google Scholar
  32. 32.
    Buccafusco JJ, Powers JC, Hernandez MA, Prendergast MA, Terry AV Jr, Jonnala RR. MHP-133, a drug with multiple CNS targets: potential for neuroprotection and enhanced cognition. Neurochem Res 2007;32: 1224–1237.CrossRefPubMedGoogle Scholar
  33. 33.
    Terry AV Jr, Gattu M, Buccafusco JJ, Sowell JW, Kosh JW. Ranitidine analog, JWS-USC-75IX, enhances memory-related task performance in rats. Drug Dev Res 1999;47:97–106.CrossRefGoogle Scholar
  34. 34.
    Paule MG, Bushnel PJ, Maurissen JPJ, et al. Symposium overview: the use of delayed matching-to-sample procedures in studies of short-term memory in animals and humans. Neurotoxicol. Teratol 1998;20:493–502.CrossRefPubMedGoogle Scholar
  35. 35.
    Esbenshade TA, Fox GB, Cowart MD. Histamine H3 receptor antagonists: preclinical promise for treating obesity and cognitive disorders. Mol Interventions 2006;6:77–88.CrossRefGoogle Scholar
  36. 36.
    Medhurst AD, Atkins AR, Beresford IJ, et al. GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer’s disease brain and improves cognitive performance in preclinical models. J Pharmacol Exp Ther 2007;321:1032–1045.CrossRefPubMedGoogle Scholar
  37. 37.
    Bonaventure P, Letavic M, Dugovic C, et al. Histamine H3 receptor antagonists: from target identification to drug leads. Biochem Pharmacol 2007;73:1084–1096.CrossRefPubMedGoogle Scholar
  38. 38.
    Fox GB, Esbenshade TA, Pan JB, et al. Pharmacological properties of ABT-239 [4-(2-(2-[(2R)-2-Methylpyrrolidinyl]ethyl)-benzofu-ran-5-yl)benzonitrile]: II. Neurophysiological characterization and broad preclinical efficacy in cognition and schizophrenia of a potent and selective histamine H3 receptor antagonist. J Pharmacol Exp Ther 2005;313:176–190.CrossRefPubMedGoogle Scholar
  39. 39.
    Akhtar M, Uma Devi P, Ali A, Pillai KK, Vohora D. Antipsychotic-like profile of thioperamide, a selective H3-receptor antagonist in mice. Fund Clin Pharmacol 2006;20:373–378.CrossRefGoogle Scholar
  40. 40.
    Cassel JC, Jeltsch H. Serotonergic modulation of cholinergic function in the central nervous system: cognitive implications. Neuroscience 1995;69:1–41.CrossRefPubMedGoogle Scholar
  41. 41.
    Terry AV Jr, Buccafusco JJ, Wilson C. Cognitive dysfunction in neuropsychiatric disorders: selected serotonin receptor subtypes as therapeutic targets. Behav Brain Res 2008;16:30–38.CrossRefGoogle Scholar
  42. 42.
    Kholdebarin E, Caldwell DP, Blackwelder WP, Kao M, Christopher NC, Levin ED. Interaction of nicotinic and histamine H3 systems in the radial-arm maze repeated acquisition task. Eur J Pharmacol 2007;56: 64–69.CrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2009

Authors and Affiliations

  1. 1.Alzheimer’s Research CenterMedical College of GeorgiaAugusta
  2. 2.Charlic Norwood VA Medical CenterAugusta

Personalised recommendations