Skip to main content
SpringerLink
Log in

Modifying peptide properties by prodrug design for enhanced transport into the CNS

  • Chapter
Peptide Transport and Delivery into the Central Nervous System

Part of the book series: Progress in Drug Research ((PDR,volume 61))

Abstract

Many central nervous system (CNS) diseases and disorders remain very difficult to treat because of the limiting effect of blood-brain barrier (BBB) on delivery of drugs into the CNS. A limited brain-uptake prevents numerous, otherwise promising agents to become pharmaceutically useful entities. Neuropeptides, their analogues and peptidomimetics are typical of these agents. Besides their poor BBB penetration, size, innate water-solubility and absence of specific transport systems to ferry them into the brain parenchyma, most peptides also have short biological half-lives because of rapid metabolism and clearance from the body [1].

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

Access this chapter

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 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
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

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Abbreviations

Ala:

alanyl

ACh:

acetylcholine

ANOVA:

analysis of variance

Arg:

arginyl

BBB:

blood-brain barrier

CDS:

chemical delivery system

CNS:

central nervous system

CSF:

cerebrospinal fluid

DADLE:

[D-Ala2,D-Leu5]enkephalin

EC:

enzyme commission

ED50 :

effective dose for 50% of the maximum activity

Gln:

glutaminyl

Glu:

glutamyl

Gly:

glycyl

His:

histidyl

IC50 :

concentration to reach 50% inhibition

IAM:

immobilized artificial membrane

i.p.:

intraperitoneal

i.v.:

intravenous

k′IAM :

IAM chromatography capacity factor

Leu:

leucyl

LHRH:

luteinizing hormone-releasing hormone

logP:

logarithm of n-octanol/water partition coefficient

MRP:

multidrug resistance-associated protein

PAM:

peptidyl α-amidating monooxygenase

PAP:

pyroglutamyl aminopeptidase

pGlu:

pyroglutamyl

Phe:

phenylalanyl

Pro:

prolyl

p-gp:

P-glycoprotein

POP:

prolyl oligopeptidase

SEM:

standard error of the mean

Ser:

seryl

t1/2 :

half-life

Thr:

threonyl

TRH:

thyrotropin-releasing hormone

TSH:

thyrotropin-stimulating hormone

Tyr:

tyrosyl

Val:

valyl

Xaa:

any amino acid residue

References

  1. Prokai L (1998) Peptide drug delivery into the central nervous system. In: EM Jucker (ed): Progress in Drug Research, Vol. 51, Birkhäuser, Basel, 96–131

    Google Scholar 

  2. Kawai M, Fukuta N, Ito N, Kagami T, Butsugan Y, Maruyama M, Kudo Y (1990) Preparation and opioid activities of N-methylated analogs of [D-Ala2, Leu5]enkephalin. Int J Pept Prot Res 35: 452–459

    Article  CAS  Google Scholar 

  3. Witt KA, Slate CA, Egleton RD, Huber JD, Yamamura HI, Hruby VJ, Davis TP (2000) Assessment of stereoselectivity of trimethylphenylalanine analogues of δ-opioid [DPhen(2), D-Pen(5)]-enkephalin. JNeurochem 75: 424–435

    Article  CAS  Google Scholar 

  4. Weber SJ, Greene DL, Sharma SD, Yamamura HI, Kramer TH, Burks TF, Hruby VJ, Hersh LB, Davis TP (1991) Distribution, and analgesia of [H-3][D-Pen2, D-Pen5]enkephalin, and two halogenated analogs after intravenous administration. J Pharm Exp Ther 259: 1109–1117

    CAS  Google Scholar 

  5. Gentry CL, Egleton RD, Gillespie T, Abbruscato TJ, Bechowski HB, Hruby VJ, Davis TP (1999) The effect of halogenation on blood-brain barrier permeability of a novel peptide drug peptides. Peptides 20: 1229–1238

    Article  PubMed  CAS  Google Scholar 

  6. Delaet NGJ, Verheyden P, Velkeniers B, Hooghepeters EL, Bruns C, Tourwe D, Vanbinst G (1993) Synthesis, biological-activity and conformational study of a somatostatin hexapeptide analog containing a reduced peptide-bond. Peptide Res 6: 24–30

    CAS  Google Scholar 

  7. Wong A, Toth I (2001) Lipid, sugar and liposaccharide based delivery systems. Curr Med Chem 8: 1123–1136.

    Article  PubMed  CAS  Google Scholar 

  8. Polt R, Palian MM (2001) Glycopeptide analgesics. Drugs Future 26: 561–576.

    Article  CAS  Google Scholar 

  9. Egleton RD, Davis TP (1997) Bioavailability and transport of peptides and peptide drugs into the brain. Peptides 18: 1431–1439

    Article  PubMed  CAS  Google Scholar 

  10. Bundgaard H (1992) Means to enhance penetration: 1. Prodrugs as a mean to improve the delivery of peptide drugs. Adv Drug Del Rev 8: 1–38

    Article  CAS  Google Scholar 

  11. Stella V (1975) Pro-drugs: an overview and definition. In: T Higuchi, VJ Stella (eds): Prodrugs as novel drug delivery systems. ACS Symposium Series, Am Chem Soc, Washington DC,1–115

    Chapter  Google Scholar 

  12. Albert A (1958) A chemical aspect of selective toxicity. Nature 182: 421–423

    Article  PubMed  CAS  Google Scholar 

  13. Harper NJ (1959) Drug latentiation. J Med Pharm Chem 1: 467–500

    Article  PubMed  CAS  Google Scholar 

  14. Sinkula AA, Yalkowsky SH (1975) Rationale for design of biologically reversible drug derivatives: Prodrugs. J Pharm Sci 64: 181–210

    Article  PubMed  CAS  Google Scholar 

  15. Stella VJ, Himmelstein KJ (1980) Prodrugs and site-specific drug delivery. J Med Chem 23: 1276–1282

    Article  Google Scholar 

  16. Stella VJ, Charman WNA, Naringrekar VH (1985) Prodrugs. Do they have advantages in clinical practice? Drugs 29: 455–473

    Article  PubMed  CAS  Google Scholar 

  17. Kearney AS (1996) Prodrugs and targeted drug delivery. Adv Drug Deliv Rev 19: 225–239

    Article  CAS  Google Scholar 

  18. Anand BS, Dey S, Mitra AK (2002) Current prodrug strategies via membrane transporters/receptors. Expert Opin Ther Biol 2: 607–620

    Article  CAS  Google Scholar 

  19. Levin VA (1980) Relationship of octanol/water partition coefficient, and molecular weight to rat brain capillary permeability. J Med Chem 23: 682–684

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  21. Abraham MH, Chadha HS, Mitchell RC (1995) Hydrogen-bonding. Part 36. Determina-tion of blood brain distribution using octanol-water partition coefficients. Drug Dis Discov 13: 123–131

    CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  23. Banks WA, Kastin AJ (1985) Peptides and the blood-brain barrier: lipophilicity as a predictor of permeability. Brain Res Bull15: 287–292

    Article  PubMed  CAS  Google Scholar 

  24. Hansch C, Bjorkroth JP, Leo A (1987) Hydrophobicity and central nervous system agents: on the principle of minimal hydrophobicity in drug design. J Pharm Sci 76: 663–687

    Article  PubMed  CAS  Google Scholar 

  25. Tatsuta T, Naito M, Oh-Hara T, Sugawara I, Tsuruo T (1992) Functional involvement of P-glycoprotein in blood-brain barrier. J Biol Chem 28: 20383–20391

    Google Scholar 

  26. Bak A, Gudmundsson OS, Friis GJ, Shiahaan TJ, Borchardt RT (1999) Acyloxy-alkoxy-based cyclic prodrugs of opioid peptides: evaluation of the chemical and enzymatic stability as well as their transport properties across Caco-2 cell monolayers. Pharm Res 16: 24–29

    Article  PubMed  CAS  Google Scholar 

  27. Begley D (1996) The blood-brain barrier: principles for targeting peptides and drugs to the central nervous system. J Pharm Pharmacol 48: 136–146

    Article  PubMed  CAS  Google Scholar 

  28. Weber SJ, Abbruscato TJ, Browson EA, Lipkowski AW, Polt R, Misicka A, Haaseth RC, Bartosz H, Hruby VJ, Davis TP (1993) Assessment of an in-vitro blood-brain-barrier model using several [NET5] enkephalin opioid analogs. J Pharm Exp 266: 1649–1655

    CAS  Google Scholar 

  29. Prokai-Tatrai K, Nguyen V, Zharikova A D, Braddy A C, Stevens SM, Jr, Prokai L (2003) Prodrugs to enhance central nervous system effects of the TRH-like peptide pG1u-GluPro-NH2. Bioorg Med Chem Lett 13: 1011–1014

    Article  PubMed  CAS  Google Scholar 

  30. Buur A, Bundgaard, H (1988) Prodrugs of peptides. III. 5-oxazolidinones as bioreversible derivatives for the α-amido carboxy moiety in peptides. Int J Pharm 46: 159–167

    Article  CAS  Google Scholar 

  31. Friis GJ, Bak A, Larsen BD, Frokjaer S (1996) Prodrugs of peptides obtained by derivatization of the C-terminal peptide bond in order to effect protection against degradation by carboxypeptidases. Int J Pharm 136: 61–69

    Article  CAS  Google Scholar 

  32. Pitman IH (1981) Pro-drugs of amides, imides and amines. Med Res Rev 1: 189–214

    Article  PubMed  CAS  Google Scholar 

  33. Bodor N, Prokai L, Wu W-M, Farag H, Jonnalagadda S, Kawamura M, Simpkins J (1992) A strategy for delivering peptides into the central nervous system by sequential metabolism. Science 257: 1698–1700

    Article  PubMed  CAS  Google Scholar 

  34. Misicka A, Maszczynska I, Lipkowski AW, Stropova D, Yamamura HI, Hruby VJ (1996) Synthesis and biological properties of gamma-glutamyl-dermorphin, a prodrug. Life Sci 58: 905–911

    Article  PubMed  CAS  Google Scholar 

  35. Amsberry KL, Borchardt, RT (1990) The lactonization of 2’-hydrocinnamic acid amides: A potential prodrug for amines. J Org Chem 55: 5867–5877

    Article  CAS  Google Scholar 

  36. Amsberry, KL, Gerstenberger, AE, Borchardt, RT (1991) Amine prodrugs which utilize hydroxy amide lactonization. II. A potential esterase-sensitive amide prodrug. Pharm Res 8: 455–461

    Article  PubMed  CAS  Google Scholar 

  37. Chen P, Bodor N, Wu WM, Prokai L (1998) Strategies to target kyotorphin analogs to the brain. J Med Chem 41: 3773–3781

    Article  PubMed  CAS  Google Scholar 

  38. Bundgaard H, Moss J (1990) Prodrugs of peptides. VI. Bioreversible derivatives of thy-rotropin-releasing hormone (TRH) with increased lipophilicity and resistance to cleavage by the TRH-specific serum enzyme. Pharm Res 7: 885–892

    Article  PubMed  CAS  Google Scholar 

  39. Bundgaard H, Rasmussen, GJ (1991) Prodrugs of peptides. 9. Bioreversible N-alpha-hydroxyalkylation of the peptide bond to effect protection against carboxypeptidases or other proteolytic enzymes. Pharm Res 8: 313–322

    Article  PubMed  CAS  Google Scholar 

  40. Klixbüll U, Bundgaard H (1984) Prodrugs as drug delivery systems. 30. 4-Imidazolidinone as potential bioreversible derivatives for the alpha-aminoamide moiety in peptides. Int J Pharm 20: 273–284

    Article  Google Scholar 

  41. Hughes JAH, Smith TV (1975) Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 258: 577–579

    Article  PubMed  CAS  Google Scholar 

  42. Malik JB, Goldstein JM (1977) Analgesic activity of enkephalins following intracerebral administration in the rats. Life Sci 20: 827–832

    Article  Google Scholar 

  43. Hambrook JM, Morgan BA, Rance MJ, Smith CF (1976) Mode of deactivation of the enkephalins by rat and human plasma and rat brain homogenate. Nature 262: 782–783

    Article  PubMed  CAS  Google Scholar 

  44. Tsuzuki N, Hama T, Hibi T, Konishi R, Futaki S, Kitagawa K (1991) Adamantane as a brain-directed drug carrier for poorly absorbed drug - antinociceptive effects of [D-Ala2]Leuenkephalin derivatives conjugated with the 1-adamantane moiety. Biochem Pharmacol 41: R5–R8

    Article  PubMed  CAS  Google Scholar 

  45. Kitagawa K, Mizobuchi N, Hama T, Hibi T, Konishi R, Futaki S (1997) Synthesis and antinociceptive activity of [D-Ala(2)]Leuenkephalin derivatives conjugated with the adamantane moiety. Chem Pharm Bull 45: 1782–1787

    Article  PubMed  CAS  Google Scholar 

  46. Fredholt K, Adrian C, Just L, Larsen DH, Weng S, Moss B, Friis GJ (2000) Chemical and enzymatic stability as well as transport properties of a Leuenkephalin analogue and ester prodrugs thereof. J Control Rel 63: 261–273

    Article  CAS  Google Scholar 

  47. Prokai L (2002) Central nervous system activity of thyrotropin-releasing hormone and its analogues. In: EM Jucker (ed): Progress in Drug Research, Vol. 59. Birkhäuser, Basel, 133–169

    Chapter  Google Scholar 

  48. Schally AV, Bowers CY, Redding TW, Barrett JF (1966) Isolation of thyrotropin releasing factor (TRF) from porcine hypothalamus. Biochem Biophys Res Commun 25: 165–169

    Article  PubMed  CAS  Google Scholar 

  49. Böler J, Enzmann F, Folkers K, Bowes CY, Schally, AV (1969) The identity of chemical and hormonal properties of the thyrotropin releasing hormone and pyroglutamyl-histidylproline amide. Biochem Biophys Res Commun 37: 705–710

    Article  PubMed  Google Scholar 

  50. Rondeel JMM, Klootwijk W, Linkels E, van de Greef WJ, Visser T (1994) Neural differentiation of the human neuroblastoma cell-line IMR32 induces production of a thyrotropin-releasing hormone-like peptide. Brain Res 665: 262–268

    Article  PubMed  CAS  Google Scholar 

  51. Ong SW, Liu HL, Pidgeon C. (1996) Immobilized-artificial-membrane chromatography: measurements of membrane partition coefficient and predicting drug membrane permeability. J Chromatogr A 728: 113–128

    Article  PubMed  CAS  Google Scholar 

  52. Prokai L, Zharikova AD, Janáky T, Li X, Braddy AC, Perjési P, Matveeva L, Powell DH, Prokai-Tatrai K (2001) Integration of mass spectrometry into early-phase discovery anddevelopment of central nervous system agents. J Mass Spectrom 36: 1211–1219

    Article  PubMed  CAS  Google Scholar 

  53. Patel ZD, McKinley BD, Davis TP, Porreca F, Yamamura HI, Hruby VJ (1997) peptide targeting and delivery across the blood-brin barrier utilizing synthetic triglyceride esters: design, synthesis and bioactivity. Bioconj Chem 8: 434–441

    Article  CAS  Google Scholar 

  54. Rasmussen GJ, Bundgaard H (1991) Prodrugs of peptides. 15. 4-Imidazolidinone prodrug derivatives of enkephalins to prevent aminopeptidase-catalyzed metabolism in plasma and adsorptive mucosae. Int J Pharm 76: 113–122.

    Article  CAS  Google Scholar 

  55. Lund L, Bak A, Friis GJ, Hovgaard L, Christrup LL (1998) The enzymatic degradation and transport of leucine-enkephalin and 4-imidazolidinone enkephalin prodrugs at the blood-brain barrier. Int J Pharm 172: 97–101.

    Article  CAS  Google Scholar 

  56. Bak A, Fich M, Larsen BD, Frokjaer S, Friis GJ (1999) N-terminal 4-imidazolidinone prodrugs of Leu-enkephalin: synthesis, chemical and enzymatic stability studies. Eur Pharm Sci 7: 317–323

    Article  CAS  Google Scholar 

  57. Bundgaard H, Moss J (1989) Prodrugs of peptides. IV. Bioreversible derivatization of the pyroglutamyl group by N-acylation and N-aminomethylation to effect protection against pyroglutamyl aminopeptidase. J Pharm Sci 78: 122–126

    Article  PubMed  CAS  Google Scholar 

  58. Moss J, Bundgaard H (1992) Prodrug peptides. 19. Protection of the pyroglutamyl residue against pyroglutamyl aminopepitidase by N-acyloxymethylation and other means. Acta Pharm Nord 4: 301–308

    PubMed  CAS  Google Scholar 

  59. Moss J, Buur A, Bundgaard H (1990) Prodrugs of peptides. 8. In vitro study of intestinal metabolism and penetration of thyrotropin-releasing hormone (TRH) and its prodrugs. Int J Pharm 66: 183–191

    Article  Google Scholar 

  60. Moss J, Bundgaard H (1991) Prodrugs of peptides. 12. Bioreversible derivatization of thy-rotropin-releasing-hormone (TRH) by N-phtalidylation of its imidazole moiety. Int J Pharm 74: 67–75

    Article  Google Scholar 

  61. Muranishi S, Sakai A, Yamada K, Murakami M, Takada K, Kiso Y (1991) Lipophilic pep-tides: synthesis of lauroyl thyrotropin-releasing hormone, and its biological activity. Pharm Res 8: 649–652

    Article  PubMed  CAS  Google Scholar 

  62. Yamada K, Murakami M, Yamamoto A, Takada K, Muranishi S (1992) Improvement of intestinal absorption of thyrotropin-releasing hormone by chemical modification with lauric acid. J Pharm Pharmacol 44: 717–721

    Article  PubMed  CAS  Google Scholar 

  63. Greene DL, Hau VS, Abbruscato TJ, Bartosz H, Misicka A, Lipkowski AW, Horn S, Gille-Spie TJ, Hruby VJ (1996) Enkephalin analog prodrugs: Assessment of in vitro conversion, enzyme cleavage characterization and blood-brain barrier permeability. J Exp Ther 277: 1366–1375

    CAS  Google Scholar 

  64. Lipkowski AW, Misicka A, Hosohata K, Davis P, Yamamura HI, Porreca F, Hruby VJ (2001) Biological properties of Phe(0)-opioid peptide analogues. Life Sci 68: 969–972

    Article  PubMed  Google Scholar 

  65. Bak A, Siahaan TJ, Gudmundsson OS, Gangwar S, Friis GJ, Borchardt RT (1999) Synthesis and evaluation of the physicochemical properties of esterase sensitive cyclic prodrugs of opioid peptides using an (acyloxy)alkoxy linker. J Peptide Res 53: 393–402

    Article  CAS  Google Scholar 

  66. Wang B, Nimkar K, Wang W, Zhang H, Shan D, Gudmundsson O, Gangwar S, Siahaan T, Borchardt RT (1999) Synthesis, and evaluation of the physichochemical properties of esterase-sensitive cyclic prodrugs of opioid peptides using coumarinic acid, and phenylpropionic acid linkers. J Peptide Res 53: 370–382

    Article  CAS  Google Scholar 

  67. Ouyang H, Borchardt RT, Siahaan TJ, Vander Velde D (2002) Synthesis and conformational analysis of a coumarinic acid-based cyclic prodrug of opioid peptide with modified sensitivity to esterase-catalyzed bioconversion. J Peptide Res 59: 183–195

    Article  CAS  Google Scholar 

  68. Liao Y, Wang B (1999) Substituted coumarins as esterase-sensitive prodrug moieties with improves release rates. Bioorg Med Chem Lett 9: 1795–1800

    Article  PubMed  CAS  Google Scholar 

  69. Hui OY, Tang FX, Siahaan TJ, Borchardt RT (2002) A modified coumarinic acid-based cyclic prodrug of an opioid peptide: its enzymatic and chemical stability and cell permeation characteristics. Pharm Res 19: 794–801

    Article  Google Scholar 

  70. Yang JZ, Chen W, Borchardt RT (2002) In vitro stability and in vivo pharmacokinetic studies of a model opioid peptide, H-Tyr-d-Ala-Gly-Phe-d-Leu-OH (DADLE), and its cyclic prodrugs. J Pharm Exp Ther 303: 840–848

    Article  CAS  Google Scholar 

  71. Shan D, Nicolaou MG, Borchardt RT, Wang B (1997) Prodrug strategies based on intratmolecular cyclization reactions. J Pharm Sci 56: 765–767

    Article  Google Scholar 

  72. Wang B, Gangwar S, Pauletti GM, Siahaan TJ, Borchardt RT (1997) Synthesis of a novelesterase-sensitive cyclic prodrug system for peptides that utilizes a “trimethyl”-lock-facilitated lactonization reaction. J Org Chem 62: 1363–1367

    Article  CAS  Google Scholar 

  73. Gudmundsson OS, Jois SD, Vander Velde DG, Shiahaan TJ, Wang B, Borchardt RT (1999) The effect of conformation on the membrane permeation of coumarinic acid-and phenylpropionic acid -based cyclic prodrugs of opioids. J Pept Res 53: 383–392

    Article  PubMed  CAS  Google Scholar 

  74. Chen W, Yang JZ, Andersen R, Nielsen LH, Borchardt RT (2002) Evaluation of the permeation characteristics of a model opioid peptide, H-Tyr-D-Ala-Gly-Phe-D-Leu-OH (DADLE), and its cyclic prodrugs across the blood-brain barrier using an in situ perfused rat brain model. J Pharmacol Exp Ther 303: 849–857

    Article  PubMed  CAS  Google Scholar 

  75. Hoek J, Rydstrom J (1988) Physiological roles of nicotinamide nucleotide transhydro-genase. J Biochem 254: 1–10

    CAS  Google Scholar 

  76. Polgar L (2002) Structure-function of prolyl oligopeptidase and its role in neurological disorders. Curr Med Chem CNS Agents 2: 251–257

    CAS  Google Scholar 

  77. Bradbury A, Finnie M, Smith D (1982) Mechanism of C-terminal amide formation of pituitary enzyme. Nature 298: 686–688

    Article  PubMed  CAS  Google Scholar 

  78. Husain I, Tate SS (1983) Formation of the COOH-terminal amide group of thyrotropin-releasing-f actor. FEBS Lett 152: 277–281

    Article  PubMed  CAS  Google Scholar 

  79. Prokai L, Prokai-Tatrai K, Bodor N (2000) Targeting drugs to the brain by chemical delivery systems. Med Res Reviews 20: 367–415

    Article  CAS  Google Scholar 

  80. Walter R, Simmons WH, Yosimoto T (1980) Proline specific endo-and exopeptidase. Mol Cell Biochem 30: 111–1277

    Article  PubMed  CAS  Google Scholar 

  81. Prokai-Tatrai K, Prokai L, Bodor N (1996) Brain-targeted delivery of a Leu-enkephalin analogue by retrometabolic design. J Med Chem 39: 4775–4782

    Article  PubMed  CAS  Google Scholar 

  82. Szirtes TL, Kisfaludi L, Palosi E, Szporny L (1984) Synthesis of thyrotropin-releasing hormone analogues. 1. Complete dissociation of central nervous system effect from thyrotropin-releasing activity. J Med Chem 27: 741–745

    Article  PubMed  CAS  Google Scholar 

  83. Jackson I (1989) Controversies in TRH biosynthesis and strategies towards the identification of a TRH precursor. Ann NY Acad Sci 553: 71–75

    Article  Google Scholar 

  84. Kahns AH, Bundgaard H (1991) Prodrugs of peptides. 13. Stabilization of peptide amides against α-chymotrypsinby the prodrug approach. Pharm Res 12: 1533–1538

    Article  Google Scholar 

  85. Bundgaard H, Kahns AH (1991) Chemical stability and plasma-catalyzed dealkylation of peptidyl-α-hydroxyglycine derivatives-intermediates in peptide a-amidation. Peptides 12: 745–748

    Article  PubMed  CAS  Google Scholar 

  86. Fischer W, Spiess J (1987). Identification of a mammalian glutaminyl cyclase converting glutaminyl into pyroglutaminyl peptides. Proc Natl Acad Sci 84: 3628–3632

    Article  PubMed  CAS  Google Scholar 

  87. Busby WH Jr, Quackenbush GE, Humm J, Youngblood W, Kizer JS (1987) An enzyme(s) that converts glutaminyl-peptides into pyroglutamyl peptides. Presence in pituitary, brain, adrenal medulla and lymphocytes. J Biol Chem 262: 8532–8536

    PubMed  CAS  Google Scholar 

  88. Prokai L, Ouyang X, Wu WM, Bodor N (1994) Chemical delivery system to transport a pyroglutamyl peptide amide to the central nervous system. J Am Chem Soc 116: 2643–2644

    Article  CAS  Google Scholar 

  89. Prokai L, Prokai-Tatrai K, Ouyang X, Kim HS, Wu WM, Zharikova AD, Bodor N (1999) Metabolism-based brain-targeting system for a thyrotropin-releasing hormone analogue. J Med Chem 42: 4563–4571

    Article  PubMed  CAS  Google Scholar 

  90. Ishikura T, Senou T, Ishihara H, Kato T, Ito T (1995) Drug delivery to the brain. DOPA prodrugs based on a ring-closure reaction to quaternary thiazolium compounds. Int J Pharm 116: 51–63

    Article  CAS  Google Scholar 

  91. Prokai L, Zharikova AD (2002) Neuropharmacodynamic evaluation of the centrally active thyrotropin-releasing hormone analogue [Leu2]TRH and its chemical brain-targeting system. Brain Res 952: 268–274

    Article  PubMed  CAS  Google Scholar 

  92. Prokai-Tatrai K, Perjesi P, Zharikova AD, Li X, Prokai L (2002) Design, synthesis and biological evaluation of novel, centrally-acting thyrotropin-releasing hormone analogues. Bioorg Med Chem Lett 12: 2171–2174

    Article  PubMed  CAS  Google Scholar 

  93. Prokai L, Prokai-Tatrai K, Zharikova AD, Nguyen V, Stevens SM Jr (2003) Centrally-act-ing and metabolically stable thyrotropin-releasing hormone analogues by replacement of histidine with substituted pyridinium. J Med Chem; in press

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, 32610, USA

    Katalin Prokai-Tatrai

  2. Department of Medicinal Chemistry, College of Pharmacy and The McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA

    Laszlo Prokai

Authors
  1. Katalin Prokai-Tatrai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laszlo Prokai
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Medicinal Chemistry, College of Pharmacy and The McKnight Brain Institute, University of Florida, 1600 S.W. Archer Road, Gainesville, FL, 32610-0497, USA

    Laszlo Prokai

  2. Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, 1600 S.W. Archer Road, Gainesville, FL, 32610-0267, USA

    Katalin Prokai-Tatrai

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Springer Basel AG

About this chapter

Cite this chapter

Prokai-Tatrai, K., Prokai, L. (2003). Modifying peptide properties by prodrug design for enhanced transport into the CNS. In: Prokai, L., Prokai-Tatrai, K. (eds) Peptide Transport and Delivery into the Central Nervous System. Progress in Drug Research, vol 61. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8049-7_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-0348-8049-7_6

  • Publisher Name: Birkhäuser, Basel

  • Print ISBN: 978-3-0348-9420-3

  • Online ISBN: 978-3-0348-8049-7

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation