Tachykinins

by Holzer, Peter; Andrews, Paul L. R. (CON); Boyce, S. (CON); Brain, Susan D. (CON); Bunnett, N. W. (CON); Canning, B. J. (CON)

• ISBN13: 9783540206903
• ISBN10: 3540206906
• Format: Hardcover
• Copyright: 2004-08-01
• Publisher: Springer Nature

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