Small Peptides - 1st Edition - ISBN: 9780444886552, 9781483164632

Small Peptides

1st Edition

Chemistry, Biology and Clinical Studies

Authors: A.S. Dutta
Editors: H. Timmerman
eBook ISBN: 9781483164632
Imprint: Elsevier
Published Date: 1st January 1993
Page Count: 632
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Description

Pharmacochemistry Library, Volume 19: Small Peptides: Chemistry, Biology, and Clinical Studies focuses on the processes, reactions, properties, and characteristics of peptides, including analogues and proteases.

The publication first takes a look at angiotensin II and bombesin/gastrin-releasing peptide. Topics include conformationally restricted analogues of bombesin, non-peptide antagonists of angiotensin II, receptor subtypes of angiotensin II, and bombesin/GRP antagonists and cancer. The text then elaborates on bradykinin, cholecystokinin, and enkephalin analogues.

The manuscript examines luteinizing hormone releasing hormone and somatostatin. Topics include enzymic degradation of somatostatin and analogues, clinical applications of somatostatin analogues, and pharmacological and clinical studies with LHRH agonists and antagonists. The formulation of peptides and inhibitors of aspartyl proteases are also mentioned.

The book is a valuable source of information for chemists, biologists, and readers interested in small peptides.

Table of Contents


Acknowledgments

Introduction

Chapter 1 Angiotensin II

1. Introduction

2. Receptor Subtypes of Angiotensin II

3. Agonist Analogues of Angiotensin II

4. Peptide Antagonists of Angiotensin II

4.1. Modifications of the C-Terminal Phe Residue

4.2. Replacement of the Tyr4 Residue

4.3. N- or C-Terminal Deletions

4.4. Interchanging the Tyr4 and Phe8 Residues

5. Non-Peptide Antagonists of Angiotensin II

5.1. Modifications of the Early Imidazole Leads

5.2. Imidazole-5-Acrylic Acid Derivatives as Antagonists of Angiotensin II

5.3. Imidazo[4,5-b]pyhdine Derivatives as Antagonists of Angiotensin II

5.4. 2-Alkyl Benzimidazole Derivatives as Antagonists of Angiotensin II

5.5. 2-Alkyl-4-(Biphenyl)Methoxyquinoline and 2,6-Dialkyl-4-(Biphenyl)Methoxy Pyridine Derivatives as Antagonists of Angiotensin II

5.6. Naphthalene, Tetrahydronaphthalene, Bromoindole and Bromobenzofuran Derivatives as Antagonists of Angiotensin II

5.7. Angiotensin Antagonists Containing an Aminomethylene Bridge

6. Non-Peptide Antagonists of Angiotensin II Acting at the AT2 Receptor

7. Summary

8. References

Chapter 2 Bombesin/Gastrin-Releasing Peptide

1. Introduction

2. Antagonists of Bombesin/GRP

2.1 Deletion of the C-Terminal Methionine Residue or the Dipeptide Leucylmethionine

2.2 Modification of the Backbone Amide Groups

2.3 Amino Acid Substitutions in Position 12

2.4 Substance P Antagonists as Bombesin Antagonists

3. Conformationally Restricted Analogues of Bombesin

4. Bombesin/GRP Antagonists and Cancer

5. Summary

6. References

Chapter 3 Bradykinin Analogues

1. Introduction

2. Receptor Subtypes of Bradykinin

3. Agonist Analogues of Bradykinin

4. Antagonists of Bradykinin

4.1. B1 Receptor Antagonists

4.2. B1 and B2 Receptor Antagonists

5. Biological Profile of HOE 140 and Related Antagonists

5.1. In Vitro Studies

5.2. In Vivo Studies

6. Side Effects Associated with Bradykinin Antagonists

7. Summary

8. References

Chapter 4 Cholecystokinin Analogues

1. Introduction

2. Distribution and Biological Functions of Cholecystokinin

3. Cholecystokinin Receptor Subtypes and Receptor-Selective Ligands

3.1. CCK-A Receptor Ligands

3.2. CCK-B Receptor Ligands

4. Peptide Antagonists of Cholecystokinin and Gastrin

4.1. Cholecystokinin and Gastrin Antagonists Based on the CCK Sequence

4.2. Antagonists Based on the Gastrin C-Terminal Sequence

4.3. Antagonists Obtained by Peptide Bond Replacements

4.4. Antagonists Containing a Homo Amino Acid Residue

4.5. Other Approaches to Antagonists

5. Non-Peptide Antagonists of CCK and Gastrin

5.1. Amino Acid Derivatives as CCK and Gastrin Antagonists

5.2. Substituted Benzodiazepines as CCK and Gastrin Antagonists

5.3. 3-Substituted-1,4-Benzodiazepines as CCK Antagonists

5.4. CCK-A Receptor Ligands Based on Tifluadom

5.5. Hybrid CCK Antagonists Based on Lorglumide and L-364,718 (MK-329)

5.6. α-Methyltryptophan Derivatives as CCK Antagonists

5.7. Quinazolinone Derivatives as CCK-B Receptor Ligands

6. Summary

7. References

Chapter 5 Enkephalin Analogues

1. Introduction

2. Enzymic Inactivation of Enkephalins

3. Early Structure Activity Relationship Studies

4. Agonist Analogues Displaying Analgesic Activity

5. Analogues with Improved Selectivity for the μ and δ Receptors

5.1. δ-Selective Analogues

5.2. μ-Selective Analogues

6. Antagonists of Enkephalins

6.1. δ-Selective Antagonists Based on the Enkephalin Sequence

6.2. μ-Selective Antagonists of Enkephalin

7. Summary

8 References

Chapter 6 Luteinising Hormone Releasing Hormone

1. Introduction

2. Enzymic Degradation of LHRH

3. Sar of LHRH Agonists

3.1 Biologically Active Analogues of LHRH Smaller than a Decapeptide

3.2 Potent Analogues of LHRH Incorporating Changes in Positions 6, 7 and 10

3.3 Potent Analogues of LHRH Incorporating α-Aza-Amino-Acid Residues

3.4 Potent Analogues of LHRH with Hydrophilic Residues in Position 6

3.5 Analogues of LHRH Containing Nitrogen Mustard Derivatives or Cytotoxic Metal Complexes

4. Sar of LHRH Antagonists

4.1 Summary of the Earlier Work

4.2 Recent Work on LHRH Antagonists

5. LHRH Antagonists and Histamine Release

6. Hexapeptide Derivatives as LHRH Antagonists

7. Ketaconazole Derivatives as LHRH Antagonists

8. Formulations of LHRH and the Analogues

9. Pharmacological and Clinical Studies with LHRH Agonists and Antagonists

9.1 Use of LHRH Agonists for the Treatment of Prostate Cancer

9.2 Use of LHRH Antagonists for the Treatment of Prostate Cancer

9.3 Use of LHRH Agonists for the Treatment of Breast Cancer

9.4 Use of LHRH Antagonists for the Treatment of Breast Cancer

9.5 Use of LHRH Agonists and Antagonists in Endomethosis

9.6 LHRH Agonists for the Treatment of Uterine Fibroids (Leiomyomata)

9.7 LHRH Agonists as Male Contraceptives

9.8 LHRH Antagonists as Male Contraceptives

9.9 LHRH Agonists as Female Contraceptives

9.10. LHRH Antagonists as Female Contraceptives

10. Summary

11. References

Chapter 7 Somatostatin

1. Introduction

2. Enzymic Degradation of Somatostatin and Analogues

3. Agonist Analogues of Somatostatin. Sar Studies

3.1 Role of the Disulphide Bridge and the N-Terminal Ala-Gly Residues

3.2 Effects of Single Amino Acid Substitutions on the Biological Activity of Somatostatin

3.3 Effects of N-Terminal Extension and Multiple Substitutions on the Biological Activity of Somatostatin

3.4 Cyclic Dodecapeptide Analogues with Amino Acid Deletions and Disulphide Bridge Modifications

3.5 Bicyclic Decapeptide and Cyclic Hexapeptide Analogues

3.6 Linear and Cyclic Octapeptide Analogues

3.7 Somatostatin Analogues as Opiate (μ-Receptor) Antagonists

4. Clinical Applications of Somatostatin Analogues

4.1 Pituitary Tumours

4.2 Pancreatic Tumours

4.3 Breast Cancer

4.4 Prostate Cancer

4.5 Lung Cancer

4.6 Mechanism of Tumour Growth Inhibition

5. Summary

6. References

Chapter 8 Tachykinins

Substance P, Neurokinin A and Neurokinin B

1. Introduction

2. Receptor Subtypes of Tachykinins

2.1 Receptor Classification Based on Tachykinins

2.2 Receptor Classification Based on Tachykinin Fragments

2.3 Receptor Classification Based on Tachykinin Antagonists

3. Sar of the Mammalian Tachykinins

3.1 Sar of the C-Terminal Fragments

3.2 Effects of Amino Acid Substitutions in Substance P

3.3 Analogues of Substance P More Selective at the NK-1 Receptor

3.4 Agonist Analogues of Neurokinin A and Neurokinin B

4. Antagonists of Substance P

4.1 Antagonists Based on the Undecapeptide Sequence

4.2 Antagonists Based on the C-Terminal Fragments

4.3. Tripeptide Derivatives as Antagonists of SP

5. Antagonists of Neurokinin A and Neurokinin B

6. Non-Peptide Antagonists of the Tachykinins

6.1. CP-96,345 Series of Substance P Antagonists

6.2. Imidazo[4,5-b]quinoxaline Series of Tachykinin Antagonists

6.3. Naphthimidazolium Derivatives as Tachykinin Antagonists

6.4. Perhydroisoindole and Androstano[3,2-b]pyhmido[1,2-a]benzimidazoles as Tachykinin Antagonists

6.5 SR 48968, an NK-2 Receptor Antagonist

6.6. NK-1 and NK-2 Selective Antagonists Obtained from Natural Products

7. Biological Studies Using SP Analogues

7.1 SP Antagonists as Analgesics

7.2 SP Antagonists in Neurogenic Inflammation

7.3 SP Antagonists in Neurogenic Bronchoconstriction

7.4 SP and Salivary Secretion

7.5 SP Antagonists in Small-Cell Carcinoma of the Lung

7.6 SP and Histamine Release

7.7 Other Biological Effects Associated with SP Antagonists. Side-Effects?

8. Summary

9. References

Chapter 9 Inhibitors of Aspartyl Proteases. 1. Renin

1. Introduction

2. Inhibitors of Renin

2.1. Inhibitors Based on the Renin Substrate

2.2. Substrate Based Inhibitors of Renin Containing a Modified Scissile Peptide Bond

2.3. Inhibitors Containing a Statine Residue in the P1 Position

2.4. Approaches Designed to Improve Potency, Stability, Oral Activity and Duration of Action of the Renin Inhibitors

2.5. Inhibitors of Renin Unrelated to the Angiotensinogen Sequence

2.6. Inhibitors of Renin Isolated From Natural Products

3. Summary

4. References

Chapter 10 Inhibitors of Aspartyl Proteases. 2. HIV Protease

1. Introduction

2. Nature of the Enzyme

3. Chemical Approaches Used in the Design of Inhibitors

3.1. Substrate Analogues Containing a Modified Scissile Peptide Bond

3.2. Inhibitors of HIV Protease Containing a Hydroxymethylcarbonyl Isostere

3.3. Inhibitors of HIV Protease Containing a Hydroxyethylamine Group

3.4. Inhibitors of HIV Protease Containing a Hydroxyethylene Isostere

3.5. Inhibitors of HIV Protease Containing a Dihydroxyethylene Isostere

3.6. Dimeric Inhibitors of HIV Protease

4 Non-Peptide Inhibitors of HIV Protease

5. Summary

6. References

Chapter 11 Metallopeptidase (Ace, Enkephalinase and Atriopeptidase) Inhibitors

1. Introduction

2. Inhibitors of Angiotensin Converting Enzyme

2.1 Ace Inhibitors with a Thiol Function as a Chelating Group

2.2 Ace Inhibitors Containing a Carboxyl Function

2.3 Phosphorus Containing Inhibitors of Ace

2.4 Glutamic Acid Derivatives as Inhibitors of Ace

2.5 Inhibitors of Ace Isolated from Natural Products

3. Inhibitors of Enkephalin Degrading Dipeptidyl- Carboxypeptidase (Enkephalinase)

3.1 Properties of Enkephalinase

3.2 Design of Enkephalinase Inhibitors

3.3 Analgesic Effects of the Enkephalinase Inhibitors

4. Inhibitors of Atrial Natriuretic Factor (ANF) Degrading Enzyme

4.1. Design of the Inhibitors

4.2. Biological and Clinical Evaluations of the ANF Degrading Metallo-Endopeptidase Inhibitors

5. Summary

6. References

Chapter 12 Formulation of Peptides

1. Introduction

2. Polymeric Controlled Drug Delivery Systems (Depot Formulations)

2.1. Depot Formulations of LHRH Analogues

2.2. Depot Formulations of Insulin

2.3. Depot Formulations of Oxytocin and Vasopressin

2.4. Depot Formulations of Growth Hormone Releasing Factor and Calcitonin

3. Improvements in the Oral Delivery of Peptides

4. Intranasal Administration of Peptides

4.1. Intranasal Formulations of LHRH Analogues

4.2. Intranasal Formulations of Insulin and Calcitonin

4.3. Intranasal Formulations of ACTH, Growth Hormone and Desmopressin

5. Transdermal Iontophoretic Drug Delivery of Peptides

6. Administration of Peptides by Ocular, Vaginal and Rectal Routes

6.1. Ocular Absorption of Peptides

6.2. Vaginal Absorption of Peptides

6.3. Rectal Absorption of Peptides

7. References

Subject Index

Details

No. of pages:
632
Language:
English
Copyright:
© Elsevier 1993
Published:
Imprint:
Elsevier
eBook ISBN:
9781483164632

About the Author

A.S. Dutta

About the Editor

H. Timmerman