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9783540206903

Tachykinins

by ; ; ; ; ;
  • ISBN13:

    9783540206903

  • ISBN10:

    3540206906

  • Format: Hardcover
  • Copyright: 2004-08-01
  • Publisher: Springer Nature
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Summary

The tachykinins represent one of the most thoroughly investigated family of neuropeptides, whose members and receptors have been characterized at the genetic and molecular level and whose pharmacology has now been advanced to the first clinical application. These exciting accomplishments and prospects are reviewed and discussed in this volume in an authoritative manner. Particular emphasis is laid on the development of selective non-peptide antagonists for all 3 tachykinin receptors and their potential as novel drugs in a variety of diseases. The approval of the first tachykinin receptor antagonist as an antiemetic drug is particularly highlighted, and the utility of tachykinin receptor antagonists in affective disorders, chronic obstructive airway disease and irritable bowel syndrome, to name a few indications, is extensively considered.

Author Biography

Peter Holzer obtained his Ph.D. in Physiology and Biochemistry from the University of Graz, Austria, in 1978. His academic career included a postdoctoral fellowship at the A.R.C. Institute of Animal Physiology and the M.R.C. Neurochemical Pharmacology Unit at the University of Cambridge, U.K., in 1980. After becoming Reader in Neuropharmacology at the University of Graz in 1985, he was a visiting scientist with the CURE Digestive Diseases Research Center at the University of California Medical School in Los Angeles, U.S.A., in 1989. In 1993 he was promoted to Professor of Neuropharmacology in the Department of Experimental and Clinical Pharmacology at the University of Graz, Austria. In 2000 Dr. Holzer declined to take the chair of Pharmacology and Toxicology at the Department of Pharmacy of the University of Innsbruck, Austria.Dr. Holzer has been holding grants from the Austrian Science Foundation, the Austrian National Bank, the Federal Ministry of Education, Science and Culture of the Republic of Austria and the Zukunftsfonds of the Province of Styria, Austria. His major research interests are in the fields of neuropharmacology, gastrointestinal pharmacology and experimental neurogastroenterology. Particular topics of research include the function of enteric neurons and primary afferent neurons in health and disease, the implication of neuropeptides and neuropeptide receptors in the regulation of gastrointestinal motility, inflammation and ulceration and the development and pharmacological characterization of experimental models with which to study dyspepsia and visceral pain. Dr. Holzer-¦s publications include more than 170 papers in peer-reviewed international journals.Dr. Holzer has been Chairman of the European Neuropeptide Club 1994 - 1996, Secretary of the IUPHAR Section of Gastrointestinal Pharmacology 1994 - 1998, and President of the Austrian Neuroscience Association 2002 - 2003. Dr. Holzer has been serving on the editorial boards of several premier journals in his field, including Neuroscience, British Journal of Pharmacology, Neurogastroenterology & Motility, Naunyn-Schmiedeberg's Archives of Pharmacology, Regulatory Peptides and Digestion.

Table of Contents

History of a Pioneering Neuropeptide: Substance P
1(24)
F. Lembeck
J. Donnerer
Extraction, Biological Testing and Structural Elucidation
1(7)
Masanori Otsuka and the Action of Substance P in the Spinal Cord
8(1)
Radioimmunoassay and Immunohistochemistry of Substance P
8(2)
Nicolas Jancso and Capsaicin
10(2)
Peptide and Nonpeptide Transmitters in Primary Afferent Neurons
12(1)
Involvement of Substance P in Autonomic and Neuroendocrine Reflexes
13(2)
Tachykinin Genes, Precursors and Receptors
15(1)
Colocalization of Substance P with Peptides and Amino Acids
15(2)
Substance P and Neurokinin A in the Gut
17(1)
Tachykinin Receptor Antagonists: The Role of Substance P Revisited
18(7)
References
19(6)
The Tachykinin Peptide Family, with Particular Emphasis on Mammalian Tachykinins and Tachykinin Receptor Agonists
25(38)
J.M. Conlon
Biosynthesis of the Tachykinins
26(4)
The Preprotachykinin A (ppt-a) Gene
26(2)
The Preprotachykinin B (ppt-b) Gene
28(1)
The Preprotachykinin C (ppt-c) Gene
28(1)
Evolution of the Preprotachykinin Genes
29(1)
Naturally Occurring and Synthetic Tachykinin Receptor Agonists
30(8)
Preprotachykinin A-Derived Peptides
30(1)
Substance P
30(3)
Neurokinin A
33(1)
Neuropeptide K
34(1)
Neuropeptide γ
35(1)
Preprotachykinin B-Derived Peptides
36(1)
Neurokinin B
36(1)
Preprotachykinin C-Derived Peptides
37(1)
Hemokinin 1
37(1)
Actions of the Tachykinins
38(25)
Preprotachykinin A-Derived Peptides
38(1)
Substance P
38(4)
Neurokinin A
42(2)
Neuropeptide K
44(1)
Neuropeptide γ
45(1)
Preprotachykinin-B Derived Peptides
46(1)
Neurokinin B
46(2)
Preprotachykinin C-Derived Peptides
48(1)
Hemokinin-1
48(1)
References
49(14)
The Histochemistry of Tachykinin Systems in the Brain
63(58)
T. Hokfelt
E. Kuteeva
D. Stanic
A. Ljungdahl
Introduction
64(3)
Historical Aspects
64(1)
Members of the Tachykinin Family
65(1)
Scope of the Present Chapter
66(1)
Aspects on Methodology
67(3)
Immunohistochemistry
67(1)
In Situ Hybridization
68(1)
Visualizing Cell Bodies and Tracing Pathways
68(1)
Specificity
69(1)
Distribution of Tachykinins
70(23)
Rat Brain
70(1)
Overview---SP/NKA and NKB Systems
70(5)
Distribution of SP/NKA Cell Bodies and Nerve Terminals
75(6)
Fiber Tracts
81(1)
Identified SP/NKA and NKB Pathways
81(2)
The Human Brain
83(2)
Telencephalon (Without Basal Ganglia)
85(2)
Basal Ganglia
87(1)
Diencephalon
87(1)
Lower Brain Stem
88(1)
Monkey Brain
89(1)
Other Species
90(1)
Coexistence of SP and Classical Transmitters
91(2)
Distribution of Tachykinin Receptors
93(8)
Rat Brain
93(1)
Overview
93(3)
Distribution of NK1 and NK3 Receptors
96(1)
Comparison Between Distribution of SP, NK1 and NK3 Receptors
97(1)
Distribution of NK2 Binding Sites
97(2)
Other Species
99(2)
General Remarks
101(20)
The Histochemical Methods
101(1)
Tachykinin Receptors
102(1)
The Mismatch Issue
102(1)
Tachykinin Circuitries
103(1)
Clinical Aspects
103(1)
References
104(17)
The Nomenclature of Tachykinin Receptors
121(20)
R. Patacchini
C.A. Maggi
Substance P and Amphibian Tachykinins: Unaware Members of a Common Family of Peptides
122(3)
Evidence for the Existence of Multiple Tachykinin Receptors, and Early Classifications
125(2)
SP-P and SP-E Receptor Classification
125(1)
SP-P, SP-K and SP-E Receptor Classification
126(1)
SP-P, SP-E and SP-N Receptor Classification
126(1)
NK-P, NK-A and NK-B Receptor Classification
127(1)
Nomenclature Committees at Work: The NK1, NK2 and NK3 Receptor Classification
127(3)
Weaknesses of the Present Nomenclature and Related Consequences
128(2)
Evidence in Favor of and Against the Existence of Further Tachykinin Receptors/Receptor Subtypes
130(3)
Variants of the Tachykinin NK1 Receptor
131(1)
Variants of the Tachykinin NK2 Receptor
131(2)
Variants of the Tachykinin NK3 Receptor
133(1)
Identification of New Mammalian Tachykinins: Hemokinin 1 and Endokinin A--D. Do They Stimulate Unknown Tachykinin Receptors?
133(2)
Conclusions
135(6)
References
136(5)
The Mechanism and Function of Agonist-Induced Trafficking of Tachykinin Receptors
141(32)
D. Roosterman
N.W. Bunnett
Introduction
142(1)
Desensitization of Tachykinin Receptors
143(6)
General Mechanisms of Desensitization of GPCRs
143(3)
Agonist-Induced Phosphorylation of Tachykinin Receptors
146(1)
Mediated Desensitization of Tachykinin Receptors
147(1)
Domains of the Tachykinin Receptors That Specify Desensitization
148(1)
Agonist Dependency of Desensitization of Tachykinin Receptors
148(1)
Agonist-Induced Endocytosis of Tachykinin Receptors
149(11)
General Mechanisms of Endocytosis of GPCRs
149(2)
Molecular Mechanisms of Agonist-Induced Endocytosis of Tachykinin Receptors
151(1)
Endocytic Domains of Tachykinin Receptors
151(1)
Interactions of Tachykinin Receptors with Arrestins
152(4)
Trafficking of Tachykinin Receptors in the Nervous System
156(3)
Endocytic Ablation of Neurons Expressing the Tachykinin NK1 Receptor
159(1)
Tachykinin Receptor Endocytosis and Mitogenic Signaling
160(3)
General Mechanisms of Arrestin-Dependent Mitogenic Signaling of GPCRs
160(1)
Arrestin-Dependent Mitogenic Signaling of the Tachykinin NK1 Receptor
161(2)
Intracellular Trafficking of Tachykinin Receptors: Resensitization and Downregulation
163(3)
General Mechanisms of Intracellular Trafficking of GPCRs
163(2)
Recycling and Resensitization of Tachykinin Receptors
165(1)
Downregulation of Tachykinin Receptors
166(1)
Conclusions
166(7)
References
167(6)
Tachykinin NK1 Receptor Antagonists
173(46)
R. Patacchini
C. A. Maggi
Introduction
174(1)
The Target Receptor
174(5)
Heterogeneity of NK1 Receptors Revealed by Selective Antagonists
175(1)
Species-Dependent Heterogeneity of the NK1 Receptor
175(2)
Intraspecies Heterogeneity of the NK1 Receptor
177(2)
Peptide Antagonists
179(8)
Early Peptide-Based SP Antagonists
179(2)
NK1 Receptor-Selective Peptide-Based Antagonists
181(6)
Nonpeptide Antagonists
187(17)
CP96345 and Related Compounds
187(4)
RP67580 and Related Compounds
191(1)
SR140333 and Related Compounds
192(1)
GR203040 and Related Compounds
193(3)
L754030 (MK869) and Related Compounds
196(2)
LY 303870 and Related Compounds
198(2)
CGP49823, SDZNKT343, NKP608
200(2)
PD154075 (CI1021)
202(1)
TAK637
203(1)
Other Nonpeptide Compounds
204(1)
Therapeutic Perspectives for NK1 Receptor Antagonists
204(15)
References
206(13)
Tachykinin NK2 Receptor Antagonists
219(26)
X. Emonds-Alt
Introduction
220(1)
Peptide-Based Tachykinin NK2 Receptor Antagonists
220(7)
Linear Peptides
220(2)
Cyclic Peptides
222(1)
Nepadutant (MEN11420)
223(3)
Cyclic Pseudopeptides
226(1)
Other Peptides
227(1)
Nonpeptide Tachykinin NK2 Receptor Antagonists
227(7)
Saredutant (SR48968)
227(4)
ZM253270
231(1)
GR159897
232(1)
SR144190
232(1)
Other Compounds
233(1)
Conclusion
234(11)
References
235(10)
Tachykinin NK3 Receptor Antagonists
245(28)
S. B. Mazzone
B. J. Canning
Introduction
246(2)
NK3 Receptor Antagonists
248(8)
Selective Nonpeptide Antagonists
252(3)
Nonselective Antagonists
255(1)
Clinical Applications for NK3 Receptor Antagonists
256(6)
Gastrointestinal Disorders
257(1)
Obstructive Airways Disease
257(2)
Cardiovascular Diseases
259(1)
Pre-eclampsia
259(1)
Somatic and Visceral Pain
260(1)
CNS Disorders
261(1)
Concluding Remarks
262(11)
References
263(10)
Combined Tachykinin NK1, NK2, and NK3 Receptor Antagonists
273(24)
W. L. Rumsey
J. K. Kerns
Introduction
274(1)
Tachykinins and the Lung
275(3)
Synergy of Combined Tachykinin Receptor Blockade in Animals
278(2)
Medicinal Chemistry Overview of Combined Antagonists
280(6)
Pharmacology of Combined Antagonists
286(3)
Nonpeptide Antagonists
286(2)
Pseudopeptide Antagonists
288(1)
Clinical Trials
289(1)
Summary
289(8)
References
290(7)
Pre-protachykinin and Tachykinin Receptor Knockout Mice
297(44)
C. A. Gadd
M. Sukumaran
S. P. Hunt
Introduction
298(1)
Distribution and Actions of Substance P
298(2)
Central Nervous System
298(1)
Peripheral Nervous System
299(1)
The Tachykinin NK1 Receptor
300(1)
Loss-of-Function Alleles of Tachykinins and Tachykinin Receptors
301(4)
Pharmacogenetics: Strategies, Cautions and Caveats
303(2)
The Effects of PPT-A or NK1 Receptor Gene Knockout
305(21)
Nociception
305(4)
Affective Behaviours
309(1)
Depression and Anxiety
309(4)
Stress
313(1)
Reward and Addiction
314(3)
Learning and Memory
317(1)
Inflammation and Response to Pathogens
317(2)
Epilepsy and Other Phenotypes
319(7)
Conclusion
326(15)
References
326(15)
Therapeutic Potential of Tachykinin Receptor Antagonists in Depression and Anxiety Disorders
341(18)
N. M. J. Rupniak
Introduction
342(1)
Substance P (NK1) Receptor Antagonists
342(9)
Clinical Trials with NK1RAs in Depression and Anxiety Disorders
343(2)
Mechanism of Action of NK1RAs in Depression
345(1)
Selectivity of NK1RAs for NK1 Receptors over Monoamine Reuptake Sites
346(1)
Substance P Levels in CSF and Plasma of Depressed Patients
346(1)
Possible Sites of Action of NK1RAs in the CNS
347(3)
Anxiolytic-Like Activity of NK1RAs in Animal Models
350(1)
NK2 Receptor Antagonists
351(1)
NK3 Receptor Antagonists
352(1)
Conclusions
352(7)
References
353(6)
The Role of Tachykinins and the Tachykinin NK1 Receptor in Nausea and Emesis
359(82)
P. L. R. Andrews
J. A. Rudd
Introduction
361(1)
The Biological and Clinical Problem of Emesis
362(8)
An Introduction to the Physiology of Nausea and Vomiting
363(1)
Motor Components
363(2)
Coordination of the Motor Components
365(1)
Triggering of the Emetic Reflex
366(3)
Nausea
369(1)
Pre-clinical Evidence for the Involvement of Tachykinins in Emesis
370(8)
Presence of Tachykinins in the Emetic Pathway
370(1)
Area Postrema
371(1)
Brain Stem Nuclei
372(1)
Vagal Afferents
373(1)
Gastrointestinal Tract
373(1)
Presence of Tachykinin Receptors in the Emetic Pathway
374(1)
Induction of Emesis by Tachykinin Receptor Agonists
375(2)
Release of Tachykinins by Emetic Stimuli
377(1)
Implication of Tachykinins in the Emetic Pathway
378(27)
Pre-clinical Models for the Study of Emesis
378(3)
Species Differences in the Pharmacology of NK1 Receptors and the Potential Complicating Role of Receptor Conformers
381(2)
Studies of the Anti-emetic Effects of NK1 Receptor Antagonists in Different Animal Models
383(1)
Studies in the Ferret
383(9)
Studies in the Dog
392(2)
Studies in the Cat
394(1)
Studies in Suncus murinus (the House Musk Shrew)
395(5)
Studies in the Piglet
400(1)
Studies in the Pigeon
401(1)
Studies in the Rat
402(1)
Summary of Pre-clinical Studies
403(2)
Clinical Evidence for the Involvement of Tachykinins in Nausea and Vomiting
405(11)
Chemotherapy-Induced Nausea and Vomiting
406(1)
CP122721 (Pfizer)
406(1)
CJ11974 (Pfizer)
407(1)
GR205171 (Glaxo-Wellcome)
408(1)
L754030 and L758298 (Merck)
408(5)
Post-operative Nausea and Vomiting
413(1)
Motion-Induced Emesis
414(1)
Summary of the Clinical Studies of the Anti-emetic Effects of NK1 Receptor Antagonists
415(1)
Site(s) and Mechanism(s) of the Anti-emetic Action of NK1 Receptor Antagonists
416(10)
Central vs. Peripheral Site of Action
416(1)
Spectrum of Anti-emetic Effects
417(1)
Central Penetration
417(2)
Central Administration
419(1)
Precise Location
419(5)
Mechanistic Considerations
424(2)
Closing Comments
426(15)
References
427(14)
Substance P (NK1) Receptor Antagonists---Analgesics or Not?
441(18)
S. Boyce
R. G. Hill
Substance P and Pain Transmission
441(1)
NK1 Receptor Antagonists in Preclinical Assays of Pain
442(5)
In Vivo Studies
442(4)
Studies in NK1 Receptor Knockout Mice
446(1)
Clinical Trials with NK1 Receptor Antagonists
447(1)
Discrepant Results of Preclinical and Clinical Trials
448(4)
Have NK1 Receptor Antagonists Been Tested in the Right Clinical Trials?
448(2)
Other Reasons for Lack of Clinical Efficacy
450(2)
Substance P Antagonists as Adjuncts to Existing Analgesics
452(7)
References
453(6)
Role of Tachykinins in Neurogenic Inflammation of the Skin and Other External Surfaces
459(32)
A. Rawlingson
S. K. Costa
S. D. Brain
Introduction
460(1)
Localization of Tachykinins, Their Receptors and Metabolizing Enzymes in Skin
461(2)
Neuron-Derived Tachykinins
461(1)
Concept of Non-neuronal Sources
462(1)
Receptors
462(1)
Release of Tachykinins in Skin
463(1)
Tachykinin Degradation in Skin
463(1)
The Classical Concept of Neurogenic Inflammation in Skin
463(1)
The Relevance of the Acute Neurogenic Inflammatory Response in Skin
464(3)
Effects on Mast Cells
464(1)
Cutaneous Blood Flow and Neurogenic Vasodilation
465(1)
Effects on Cutaneous Microvascular Permeability and Oedema Formation
466(1)
Effect of Tachykinins on Leukocyte-Endothelial Cell Interactions
467(3)
Role of Mast Cells in Polymorphonuclear Leukocyte Accumulation
467(1)
Direct Neutrophil Activation by Tachykinins
468(1)
Tachykinins and Eosinophils
469(1)
Tachykinins and Endothelial Cell Adhesion Molecules
469(1)
NK1 Receptor-Mediated Neutrophil Recruitment in Animal Models
469(1)
Tachykinins and their Contribution to Ongoing Immune Processes in Skin
470(2)
Lymphocytes
470(1)
Monocytes
471(1)
Keratinocytes
471(1)
Fibroblasts
472(1)
Tachykinins in Non-mammalian Skin and Naturally Occurring Toxins and Venoms
472(2)
Arachnids
472(1)
Reptiles and Amphibians
473(1)
Microbial Toxins
474(1)
Evidence for Tachykinin Involvement in Human Skin Disease
474(4)
Psoriasis
475(1)
Dermatitis
475(1)
Pruritus
476(1)
Urticaria
477(1)
Other Skin Diseases
477(1)
Wound Healing
478(1)
Conclusions
479(12)
References
479(12)
Role of Tachykinins in Obstructive Airway Disease
491(20)
G. F. Joos
Introduction
492(1)
Tachykinins in Human Airways
493(2)
Airway Tachykinin Receptors
495(1)
Bronchoconstrictor Effects of Tachykinins
496(2)
Airway Plasma Extravasation
498(1)
Tachykinins and Allergen-Induced Airway Responses
499(1)
Involvement of Tachykinins in Animal Models of Asthma and COPD
500(1)
Plasticity of Tachykinergic Airway Innervation
500(1)
Tachykinin Receptor Antagonists as a Potential New Treatment for Obstructive Airway Diseases
501(2)
Conclusions and Future Perspectives
503(8)
References
504(7)
Role of Tachykinins in the Gastrointestinal Tract
511(48)
P. Holzer
Introduction
512(1)
Expression of Tachykinin Genes in the Gut
513(1)
Cellular Localization of Tachykinins in the Gut
514(4)
Neuronal Sources of Tachykinins in the GI Tract
514(3)
Non-neuronal Sources of Tachykinins in the GI Tract
517(1)
Cellular Expression of Tachykinin Receptors in the Gut
518(1)
Functional Implications of Tachykinins in the Gut
519(7)
Transmitter Function
519(2)
Motor Regulation
521(2)
Secretion of Hormones, Enzymes, Electrolytes and Fluid
523(2)
Blood Flow, Vascular Permeability and Immune Cell Function
525(1)
Tachykinins and Tachykinin Receptors in Gastrointestinal Disorders
526(12)
Pathological Changes in Tachykinin Expression
526(2)
Pathological Changes in Tachykinin Receptor Expression
528(1)
Motor Disturbances
529(3)
Hypersecretion and Inflammation
532(4)
Hyperalgesia and Pain
536(2)
Summary
538(21)
References
539(20)
Subject Index 559

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