Skip to main content
SpringerLink
Log in
Book cover

Blood—Brain Barrier pp 281–309Cite as

Optimizing Drugs for Brain Action

  • Chapter

Abstract

The cost of developing a new drug from conception in the laboratory, through in vitro and in vivo studies and then through required clinical trials to final approval by the United States Food and Drug Administration or its European equivalent, for wide clinical use is in excess of several hundred million dollars. With a changing health care environment, stiff market place competition and high infrastructure costs involved in pharmaceutical research, development and marketing, drug development represents an enormous investment of money and resources. Matching this, the process of drug development within the pharmaceutical industry is changing to favor a “high tech”, efficient and, primarily, ex vivo approach by using molecular biology to characterize and often patent new, hopefully critical and ratelimiting subcellular targets and high throughput combinatorial chemistry to generate libraries of multiple thousands of compounds for screening. With such financial investment, a focus has been towards the rapid development of billion dollar drugs in large patient populations. There have been successful examples of this development system. However, these must be counterbalanced by the knowledge that (i) when the wrong avenue is chosen in the development scheme it can be hugely costly, and the presence of the blood-brain barrier (BBB) certainly complicates the choice of avenues, and (ii) it is unlikely that new therapeutics will be specifically designed and developed for numerous crippling and fatal diseases in smaller patient populations, which includes many neurological diseases. Certainly, some new therapeutics will prove beneficial for use in diseases other than the ones for which they were specifically designed and developed, but when this occurs it can be considered fortuitous rather than planned. Despite this, it is clear that better use of the drugs that we already have available is required if treatment advances are to be made.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Abraham MH., 1993, Scales of solute hydrogen bonding: their construction and application to physicochemical and biochemical processes. Chem. Soc. Rev. 22: 73–83.

    Article  CAS  Google Scholar 

  • Abraham MH, Chadha HS., 1996, Applications of solvation equations to drug transport properties. In, Liophilicity in Drug Action and Toxicity (Pliska V, Testa B, Van de Waterbeem E, eds) VCH, Weinheim, Germany, pp 311–337.

    Chapter  Google Scholar 

  • Ali-Osman F, Greig NH, John V, Lieberburg IM., 1991, Activity of tertiary butyl chlorambucil ester against 2-chloroethylnitrosourea-resistant human malignant glioma cell lines. Proc. Am. Assoc. Cancer Res. 32: 318.

    Google Scholar 

  • Asthana S, Greig NH, Hegedus L, Holloway HW, Raffaele K, Schapiro M, Soncrant TT., 1995, Clinical pharmacokinetics of physostigmine in pateints with dementia of the Alzheimer’s type. Clin. Pharmacol. Ther. 58: 299–309.

    Article  PubMed  CAS  Google Scholar 

  • Asthana S, Greig NH, Holloway HW, Raffaele K, Schapiro M, Soncrant TT., 1996, Clinical pharmacokinetics of the muscarinic agonist arecoline in Alzheimer’s disease. Clin. Pharmacol Ther. 60: 276–282.

    Article  PubMed  CAS  Google Scholar 

  • Barber KL, Mesulam MM, Kraft GA, Klein WL., 1996, Butyrylcholinesterase Alters the Aggregation of A? Amyloid. Proc. Soc. Neurosci., 22: 1172.

    Google Scholar 

  • Bartus RT, Dean RL, Beer B., 1980, Memory deflcts in aged cebus monkeys and facilitation with central cholinomimetics. Neurobiol. Aging 1: 145–152.

    Article  CAS  Google Scholar 

  • Bartus, RT, Dean R., Beer B, Lippa AS., 1982, The cholinergic hypothesis of geriatric memory dysfunction. Science 217, 408–417.

    Article  PubMed  CAS  Google Scholar 

  • Becker RE, Giacobini E., 1988, Mechanisms of Cholinesterase inhibition in senile dementia of Alzheimer’s type: clinical, pharmacological and therapeutic aspects. Drug Dev. Res. 12: 163–195.

    Article  CAS  Google Scholar 

  • Becker R, Moriarty P, Unni L., 1991, The second generation of Cholinesterase inhibitors: clinical and pharmacological effects, in: “Cholinergic Basis of Alzheimer’s Disease, ” R. Becker, E. Giacobini, ed., Birkhauser, Boston, pp 263–296.

    Google Scholar 

  • Becker RE, Moriearty P, Unni L, Vicari S., 1997, Cholinesterase inhibitors as therapy in Alzheimer’s disease: benefit to risk considerations in clinical application. In, Alzheimer’s Disease: Molecular Biology to Therapy (ed, Becker, R. & Giacobini, E), Birkhäuser, Boston, pp 257–268.

    Google Scholar 

  • Blusztajn JK, Wurtman RJ., 1983, Choline and cholinergic neurons. Science 221, 614–621.

    Article  PubMed  CAS  Google Scholar 

  • Bradbury MWB., 1979, “Concept of a Blood-Brain Barrier, ” John Wiley, Chichester.

    Google Scholar 

  • Bradbury MWB., 1992, “Physiology and Pharmacology of the Blood-Brain Barrier, ” Handbook of Experimental Pharmacology Vol. 103, Springer Verlag, Berlin.

    Google Scholar 

  • Brozostowska M, He XS, Greig NH, Rapoport S, Brossi A., 1992, Phenylcarbamates of (-)-eseroline, (-)-Nl-noreseroline and (-)-physovenol: selective inhibitors of acetyl-and, or butyrylcholinesterase. Med. Chem. Res. 2: 238–246.

    Google Scholar 

  • Brufani M, Filoccamo L., 2000, Rational design of Cholinesterase inhibitors. In, Cholinesterases and Cholinesterase Inhibitors (ed, Giacobini E) Martin Dunitz, London, pp 27–46.

    Google Scholar 

  • Calabresi P, Schein PS., 1993, “Medical Oncology, Basic Principles and Clinical Management, ” McGraw-Hill, New York.

    Google Scholar 

  • Chatanet A, Lockridge O., 1989, Comparison and butyrylcholinesterase and acetylcholinesterase. Biochem. J. 260: 625–634.

    Google Scholar 

  • Dagenais C, Rousselle C, Pollack GM, Scherrmann JM., 2000, Development of an in situ mouse brain perfusion model and its application to mdrl a p-glycoprotein-deficient mice. J. Cereb. Bllod Flow Meatbol. 20: 381–386.

    Article  CAS  Google Scholar 

  • Davies P, Maloney AJF., 1976, Selective loss of central cholinergic neurons in Alzheimer’s type dementia. Nature 288: 279–280.

    Article  Google Scholar 

  • Diamond JM, Wright EM., 1969, Molecular forces governing non-electrolyte permeation through cell membranes. Proc. Royal Soc. London [Biol] 172: 273–316.

    Article  CAS  Google Scholar 

  • Drachman DA, Leavit J., 1974, Human memory and the cholinergic system. Arch. Neurol. 30: 113–121.

    Article  PubMed  CAS  Google Scholar 

  • Ehrsson H, Lonroth U, Wallin I, Ehrnebo M, Nilsson S., 1981, Degradation of chlorambucil in aqueous solution: influence of human albumin binding. J. Pharm. Pharmacol. 33: 313–315.

    Article  PubMed  CAS  Google Scholar 

  • Fenstermacher JD., 1992, The blood-brain barrier is not a barrier for many drugs. NIDA Res. Mongr. 120: 108–120.

    CAS  Google Scholar 

  • Fenstermacher J.D; Cowles AL., 1977, Theoretic limitations of intracarotid infusions in brain tumor chemotherapy. Cancer Treat. Rep. 61: 519–526.

    PubMed  CAS  Google Scholar 

  • Fenstermacher JD, Gross P, Sposito N, Acuff V, Petersen S, Gruber K., 1988, Structural and functional variations in capillary systems within the brain. Ann. NY Acad. Sci. 529: 21–30.

    Article  PubMed  CAS  Google Scholar 

  • Genka S, Shetty U, Stahle PL, John V, Lieberburg IM, Ali-Osman F, Rapoport S, Greig NH., 1993, Development of lipophilic anticancer agents for the treatment of brain tumors by the esterification of water-soluble chlorambucil. Clin. Exp. Metastasis 11: 131–140.

    Article  PubMed  CAS  Google Scholar 

  • Giacobini E., 1997, Cholinesterase inhibitors do more than inhibit Cholinesterase. In, Alzheimer’s Disease: Molecular Biology to Therapy (ed, Becker, R. & Giacobini, E), Birkhäuser, Boston, pp 188–204.

    Google Scholar 

  • Giacobini E., 2000, Cholinesterase inhibitors: from the Calabar bean to Alzheimer therapy. In, Cholinesterases and Cholinesterase Inhibitors (ed, Giacobini E) Martin Dunitz, London, 181–226.

    Google Scholar 

  • Gollapudi S. Kim CH, Tan BN, Sangha S, Gupta S., 1997, Probenecid reverses multidrug resistance in multidrug resistance-associated protein overexpressing HL60/AR and H69/AR cells but not in P-glycoprotein overexpressing HL60/Tax and P388/ADR cells. Cancer Chemother. Pharmacol. 40: 150–158.

    Article  PubMed  CAS  Google Scholar 

  • Gottesman MM, Pastan I., 1993, Biochemistry of multidrug resistance mediated by the multidrug transporter. Ann. Rev. Biochem. 62: 385–427.

    Article  PubMed  CAS  Google Scholar 

  • Greig NH., 1984, Chemotherapy of brain metastases: current status. Cancer Treat. Rev. 11: 157–186.

    Article  PubMed  CAS  Google Scholar 

  • Greig NH., 1987, Optimizing drug delivery to brain tumors. Cancer Treat. Rev. 14: 1–28.

    Article  PubMed  CAS  Google Scholar 

  • Greig NH., 1989a, Drug delivery to the brain by blood-brain barrier circumvention and drug modification, in: “Implications of the blood-brain barrier and its modification, Vol. 1, Basic science studies, ” E.A. Neuwelt, ed., Plenum Press, New York, pp 311–367.

    Chapter  Google Scholar 

  • Greig NH., 1989b, Brain tumors and the blood-tumor barrier, in: “Implications of the blood-brain barrier and its modification, Vol. 2, Clinial studies, ” E.A. Neuwelt, ed., Plenum Press, New York, pp 77–106.

    Chapter  Google Scholar 

  • Greig NH., 1992, Drug entry into the brain and its pharmacologic manipulation, in: “Physiology and Pharmacology of the Blood-Brain Barrier, Handbook of Experimental Pharmacology Vol. 103, ” M.W.B. Bradbury, ed., Springer Verlag, Berlin, pp 489–523.

    Google Scholar 

  • Greig NH, Momma S, Sweeney DJ, Smith QR, Rapoport S., 1987, Facilitated transport of melphalan at the rat blood-brain barrier by the large neutral amino acid transport system. Cancer Res. 47: 1571–1576.

    PubMed  CAS  Google Scholar 

  • Greig NH, Sweeney DJ, Rapoport S., 1988, Comparative brain and plasma pharmacokinetics of chlorambucil and melphalan in the rat. Cancer Chemother. Pharmacol. 21: 1–8.

    Article  PubMed  CAS  Google Scholar 

  • Greig NH, Ries L, Yancik R, Rapoport S., 1990b, Increasing annual incidence of primary malignant brain tumors in the elderly. J. Natl. Cancer Inst. 82: 1621–1623.

    Article  PubMed  CAS  Google Scholar 

  • Greig NH, Genka S, Rapoport, S., 1990c, Delivery of vital drugs to the brain for the treatment of brain tumors. J. Controlled Release 11: 61–78.

    Article  CAS  Google Scholar 

  • Greig NH, Genka S, Daly EM, Sweeney DJ, Rapoport S., 1990d, Physicochemical and pharmacokinetic parameters of seven lipophilic chlorambucil esters designed for brain penetration. Cancer Chemother. Pharmacol. 25: 311–319.

    Article  PubMed  CAS  Google Scholar 

  • Greig NH, Daly EM, Sweeney DJ, Rapoport S., 1990e, Pharmacokinetics of chlorambucil tertiary butyl ester, a lipophilic chlorambucil derivative that achieves and maintains high concentrations in brain. Cancer Chemother. Pharmacol. 25: 320–326.

    Article  PubMed  CAS  Google Scholar 

  • Greig NH, DeMicheli E, Holloway HW, Yu QS, Perry TA, Deutsch J, Ingram D, Lahiri DK, Soncrant, TT, 2000, The experimental Alzheimer drug phenserine: pharmacodynamics and kinetics in the rat. Acta Neurol. Scand. 102: 74–84.

    Article  Google Scholar 

  • Greig NH, Ingram D, Wallace WC, Utsuki T, Yu, QS, Holloway HW, Pei XF, Haroutunian, V, Lahiri DK, Brossi A, Soncrant TT., 1997, Phenserine: a selective, long-acting abd brain-directed acetylcholinesterase inhibitor affecting cognition and D-APP processing. In, Alzheimer’s Disease: Molecular Biology to Therapy (eds, Becker, R; Giacobini, E, Robert, P), Birkhauser, Boston, pp 231–237.

    Google Scholar 

  • Greig, NH, Pei XF, Soncrant TT, Ingram DK, Brossi A., 1995, Phenserine and Ring C Hetero-Analogues: Drug Candidates for Treatment of Alzheimer’s Disease. Med. Res. Rev. 15: 3–31.

    Article  PubMed  CAS  Google Scholar 

  • Guillozet AL, Smiley JF, Mash DC, Mesulam MM., 1997, Butyrylcholinesterase in the Life Cycle of Amyloid Plaques. Ann. Neurol., 42: 909–918.

    Article  PubMed  CAS  Google Scholar 

  • Habgood MD, Begley DJ, Abbott NJ., 2000, Determinants of passive drug entry into the central nervous system. Cell Mol. Neurobiol. 20: 231–253.

    Article  PubMed  CAS  Google Scholar 

  • Hamilton-Miller J., 1967, Chemical manipulations of the penicillin nucleus: a review. Chemotherapia. 12: 73–88.

    Article  CAS  Google Scholar 

  • Hardebo JE, Owman C., 1991, Enzymatic barrier mechanisms for neurotransmitter monoamines and their precurrsors at the blood-brain barrier., in: “Pathophysiology of the Blood-Brain Barrier, ” B.B. Johansson, C. Owman, H, Widner, ed. Elsevier, Amsterdam, pp 71–82.

    Google Scholar 

  • Harel M, Sussman JL, Krejci E, Bon S, Chanal P, Massoulie J, Silman I. 1992, Conversion of acetylcholinesterase to butyrylcholinesterase: modeling and mutagenesis. Proc. Natl. Acad. Sci. USA 89: 10827–10831.

    Article  PubMed  CAS  Google Scholar 

  • Iijima S, Greig NH, Garofalo P, Spangler EL, Heller B, Brossi A, Ingram DK., 1993, Phenserine: a physostigmie derivative that is a long-acting inhibitor of Cholinesterase and demonstrates a wide dose range for attenuating a scopolamine-induced learning impairment of rats in a 14-unit T-maze. Psychopharmacol. 112: 415–420.

    Article  CAS  Google Scholar 

  • Ingram DK, Spangler EL, Iijima S, Kuo H, Bresnahan EL, Greig NH, London ED., 1994, New pharmacological strategies for cognitive enhancement using a rat model of agerelated memory impairment. Annals NY Acad, Sci. 717: 16–32.

    Article  CAS  Google Scholar 

  • Ikari H, Spangler E, Greig NH, Pei XF, Brossi A, Speer D, Patel N, Ingram, DK, 1995, Performance of aged rats in a 14-unit T-maze is improved following chronic treatment with phenserine, a novel long-acting anticholinesterase. NeuroReport 6: 481–484.

    Article  PubMed  CAS  Google Scholar 

  • Jansen A, Russell T., 1965, Some novel penicillin derivatives. J. Chem. Soc. 2127–2132.

    Google Scholar 

  • Jones DR, Hall SD, Jackson EK, Branch RA, Wilkinson GR., 1988, Brain uptake of benzodiazepines: effects of lipophilicity and plasma protein binding. J. Pharmacol. Exp. Ther. 245: 816–822.

    PubMed  CAS  Google Scholar 

  • Knapp MJ, Knopman DS, Solomon PR, Penlebury WW, Davies CS, Gracon SI., 1994, A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer’s disease. JAMA 271: 985–991.

    Article  PubMed  CAS  Google Scholar 

  • Lautier D, Canitrot Y, Deeley RG, Cole S., 1996, Multidrug resistance mediated by the multidrug resistance protein gene. Biochem. Pharmacol. 52: 967–977.

    Article  PubMed  CAS  Google Scholar 

  • Lehman DJ, Johnston C, Smith AD, 1997, Synergy Between Genes for Butyrylcholinesterase K Variant and Apolipoprotein E4 in Late-Onset Confirmed Alzheimer’s Disease. Human Mol. Genetics 6: 1933–1936.

    Article  Google Scholar 

  • Leo A, Hansch C, Elkins D., 1971, Partition coefficients and their uses. Chem. Rev. 71: 525–616.

    Article  CAS  Google Scholar 

  • Levin VA., 1980, Relation of octanol/water partition and molecular weight to rat brain capillary permeability. J. Med. Chem. 23: 682–684.

    Article  PubMed  CAS  Google Scholar 

  • Long, JP., 1963, Structure-activity relationships of the reversible anticholinesterase agents. In, Cholinesterase and Anticholinesterase Agents. In, Handbach der Experimentellen Pharmakologie, Vol. 15. (ed. Koelle, G.B.) Springer-Verlag, Berlin, pp.374–427.

    Google Scholar 

  • Massoulie J, Sussman J, Bon S, Siman I., 1993, Structure and functions of acetylcholinesterase and butyrylcholinesterase. Prog. Brain Res. 98: 139–146.

    Article  PubMed  CAS  Google Scholar 

  • Newhouse PA, Sunderland T, Tariot PN, Blumhardt MA, Weingartner H, Mellow A., 1988, Intravenous nicotine in Alzheimer’s disease: a pilot study. Psychopharmacol. 95: 171–175.

    CAS  Google Scholar 

  • Oliverio V., 1976, Pharmacology of the nitrosoureas: an overview. Cancer Treat. Rep. 60: 703–707.

    PubMed  CAS  Google Scholar 

  • O’Neill J, Halgren E, Markinovic K, Siembieda D, Refai D, Fitten LJ, Perryman K, Fisher A., 2000, Effects of muscarinic and adrenergic agonism on auditory P300 in the macaque. Physiol. Behav. 70: 163–170.

    Article  PubMed  Google Scholar 

  • Ordentlich A, Barak D, Kronan C, Flashner Y, Leitner M, Segall Y, Ariel N, Cohen S, Velan B, Shafferman A. 1993, Dissection of the human acetylcholinesterase active center determinants of substrate specificity. J. Biol Chem., 268: 17083–17095.

    PubMed  CAS  Google Scholar 

  • Pardridge WM., 1999, Blood-brain barrier biology and methodology. J. Neurovirol 5: 556–569.

    Article  PubMed  CAS  Google Scholar 

  • Pardridge WM., 1998, CNS drug design based on principles of blood-brain barrier transport. J. Neurochem. 70: 1781–1792.

    Article  PubMed  CAS  Google Scholar 

  • Patel N, Spangler E, Greig NH, Yu QS. Ingram DK, Myer, RC., 1998, Phenserine, a novel acetylcholinesterase inhibitor, attenuates impaired learning of rats in a 14-unit T-maze induced by the blockade of the N-methyl-D-aspartate receptor. Neuroreport, 9: 171–176.

    Article  PubMed  CAS  Google Scholar 

  • Perry EK, Tomlinson BE, Blessed G, Bergman K. Gibson PH, Perry RH., 1978, Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia Brit. Med. J. 2: 1457–1459.

    Article  PubMed  CAS  Google Scholar 

  • Posner J., 1977, Management of central nervous system metastases Semin. Oncol. 4: 81–91.

    PubMed  CAS  Google Scholar 

  • Quinn DM., 1987, Acetylcholinesterase: enzyme structure, reaction dynamics, and virtual transition states. Chem. Rev. 87: 955–979.

    Article  CAS  Google Scholar 

  • Reese T, Karnovsky M., 1967, Fine structural localization of a blood-brain barrier to exogenous peroxidase. J. Cell Biol. 34: 207–217.

    Article  PubMed  CAS  Google Scholar 

  • Reiner E, Radic Z. 2000, Mechanism of action of Cholinesterase inhibitors. In, Cholinesterases and Cholinesterase Inhibitors (ed, Giacobini E) Martin Dunitz, London, pp 103–120.

    Google Scholar 

  • Silman I, Harel M, Eichler J, Sussman JL, Anselmet A, Massoulie J., 1994, Structure-activity relationship in the binding of reversible inhibitors in the active-site gorge of acetylcholinesterase. In, Alzheimer’s Disease: Therapeutic Strategies (ed, Becker, R. & Giacobini, E), Birkhäuser, Boston, pp 88–92.

    Google Scholar 

  • Silman I, Sussman JL., 2000, Structural studies of acetylcholinesterase. In, Cholinesterases and Cholinesterase Inhibitors (ed, Giacobini E) Martin Dunitz, London, pp 9–26.

    Google Scholar 

  • Somani SM, Kahlique A., 1986, Distribution and pharmacokinetics of physostigmine in rat after intramuscular administration. Fund. Appl. Toxicol. 6: 327–334.

    Article  CAS  Google Scholar 

  • Soncrant TT, Raffaele KC, Asthana A., 1993, Memory improvement without toxicity during chronic low dose intravenous arecoline in Alzheimer’s disease. Psychopharmacol. 112: 421–428.

    Article  CAS  Google Scholar 

  • Soreq H, Zakut H., 1990, Amplification of butyrylcholinesterase and acetylcholinesterase genes in normal and tumor tissues: putative relationship to organophosphorous poisoning. Pharmaceutic. Res. 7: 1–7.

    Article  CAS  Google Scholar 

  • Soreq H, Zakut H., 1993, “Human Cholinesterases and Anticholinesterases, ” Academic Press, New York.

    Google Scholar 

  • Smith QR., 1995, Carrier mediated drug transport at the blood-rain barrier and the potential for drug targeting to the brain. In, New Concepts of a Blood-Brain Barrier (Greenwood J, Begley D, Segal M, eds), Plenum Press, New York, pp 265–276.

    Google Scholar 

  • Sussman JL, Harel M, Farlow F, Oefner C, Goldman A, Toker L, Silman I., 1991, Atomic structure of acetylcholinesterase from Torpedo Californica: a prototypic acetylcholinebinding protein. Science 253: 872–879.

    Article  PubMed  CAS  Google Scholar 

  • Takada T, Vistica DT, Greig NH, Rapoport S, Smith QR., 1992, Rapid high-affinity transport of nitrogen mustard amino acid across the blood-brain barrier. Cancer Res. 52: 2191–2196.

    PubMed  CAS  Google Scholar 

  • Taylor P., 1991, The cholinesterases. J. Biol. Chem., 266: 4025–4028.

    PubMed  CAS  Google Scholar 

  • Taylor P, Radic Z., 1994, The cholinesterases: from genes to proteins. Ann. Rev. Pharmacol. Toxicol., 34: 281–320.

    Article  CAS  Google Scholar 

  • Teraski T, Pardridge WM., 1988, Restricted transport of 3’-azido-deoxythymidine and dideoxynucleosides through the blood-brain barrier. J. Infect. Dis. 158: 630–632.

    Article  Google Scholar 

  • Torrence P, Kinjo J, Khamnei S, Greig NH., 1993, Synthesis and pharmacokinetics of a dihydropyridine chemical delivery system for the antiimmunodeficiency virus agent dideoxycytidine. J. Med. Chem. 36: 529–537.

    Article  PubMed  CAS  Google Scholar 

  • Tyson G, Fenstermacher JD, Davis R., 1989, Vascular factors affecting drug delivery to brain tumors. Basic Life Sci. 50: 115–120.

    PubMed  CAS  Google Scholar 

  • Usdi, E., 1970, Reactions of Cholinesterase with substrates, inhibitors and reactivators. In, Anticholinesterase Agents, Vol. 1. International Encyclopedia of Pharmacology and Therapeutics, Sec. 13. (ed. Karczmar, A.G.) Pergamon Press, Ltd., Oxford, pp. 47–354.

    Google Scholar 

  • Vellom DC, Radic Z, Li Y, Pickering NA, Camp S, Taylor P. 1993, Amino acid residues controlling acetylcholinesterase and butyrylesterase specificity. Biochem. 32: 12–17.

    Article  CAS  Google Scholar 

  • Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, DeLong MR., 1982, Alzheimer’s disease and senile dementia: a quantitative study. Science 215: 1237–1239.

    Article  PubMed  CAS  Google Scholar 

  • Yu QS Liu C, Brzostowska M, Chrisey L, Brossi A, Greig NH, Atack JR, Soncrant TT, Rapoport S, Radunz HE., 1991, Physovenines: efficient synthesis of (-)-and (+)-physovenine and synthesis of carbamate analogues of (-)-physovenine. Anticholinesterase activity and analgesic properties of optically active physovenines. Helv. Chim. Acta 74: 761–767.

    Article  CAS  Google Scholar 

  • Yu QS, Greig NH, Holloway HW, Flippen-Anderson F, Brossi A., 2000, (-)-(3aS)-Eseroline carbamate (II), a potent Cholinesterase inhibitor and close analogue of physostigmine: reanalysis. Med. Chem. Res. 10: 186–199.

    CAS  Google Scholar 

  • Yu, QS, Holloway HW, Flippen-Anderson F, Brossi A, Greig NH., 2001, Methyl analogues of the experimental Alzheimer drug, phenserine: synthesis and structure/activity relationships for acetyl-and butyrylcholinesterase inhibitory action. J. Med. Chem in press.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, 21224, USA

    Nigel H. Greig, Qian-Sheng Yu, Tadanobu Utsuki, Harold W. Holloway, Xiaoxiang Zhu, Tracyann Perry, Bong Ho Lee & Donald K. Ingram

  2. Department of Psychiatry & Neurology, Indiana University School of Medicine, Indianapolis, IN, USA

    Debomoy K. Lahiri

Authors
  1. Nigel H. Greig
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qian-Sheng Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tadanobu Utsuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Harold W. Holloway
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaoxiang Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tracyann Perry
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bong Ho Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Donald K. Ingram
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Debomoy K. Lahiri
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Israel Institute for Biological Research, Ness-Ziona, Israel

    David Kobiler , Shlomo Lustig  & Shlomo Shapira ,  & 

Rights and permissions

Reprints and permissions

Copyright information

© 2001 Springer Science+Business Media New York

About this chapter

Cite this chapter

Greig, N.H. et al. (2001). Optimizing Drugs for Brain Action. In: Kobiler, D., Lustig, S., Shapira, S. (eds) Blood—Brain Barrier. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0579-2_24

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-0579-2_24

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-5141-2

  • Online ISBN: 978-1-4615-0579-2

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation