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The tachykinin receptors
B Something of substance The Tachykinin Receptors edited by Stephan H. Buck, Humana Press, 1994. $125.00 (xi + 630 pages) ISBN 0 89603 266 3
This is a substantial volume, the latest in a series on topical neurotransmitter receptors, and is arranged in nineteen chapters each by different international authorities in a particular area. It attempts, with some success, to review current understanding in this extensive and ever expanding area, and is surprisingly the first book to attempt this task, even though substance I’ was the first neuropeptide described (1931) and its receptor was the first neuropeptide receptor to be cloned (1987). The emphasis of this book is very much on receptors rather than their ligands, although there have been notable recent successes in the latter area. However, because selective receptor agonists and antagonists are still the main means of defining the properties of receptors, it is inevitable that such drugs are discussed in this context in many of the chapters. Only mammalian tachykinins and their receptors are within the remit of the book. However, over fifty tachykinins have been identified from a number of different animal families, and hence some nonmammalian peptides (for example, eledoisin, kassinin and physalaemin) and their receptors are discussed. In fact, it can be argued that some phylogenetic awareness is invaluable, since mutation and evolution can subtly alter both the signal molecule and the receptor and provide information on the essential chemical features necessary for binding of ligands and of the receptor. These earlier studies have been rapidly augmented by the various techniques of molecular biology, which are discussed primarily by James Krause rt ol. in an excellent chapter.
A recent hot topic of debate concerns heterogeneity in a given class of mammalian tachykinin receptors, either between species (proven), or within species (possible). This is an important and as yet unresolved issue in the development of drugs intended for human therapeutics from animal studies, and is the subject of an excellent and detailed chapter (Carlo Maggi). For example, in terms of the discovery of the first high-affinity nonpeptide antagonist, it is fortunate that humans are more like cows than rats in this respect, since binding to bovine brain tissue was used in the high-throughput non-rational screen used in the discovery of this ligand. It is necessary to trawl the book to determine whether the often supposed correlation between each of the three main mammalian tachykinins (substance I’, neurokinin A and neurokinin B) and the three clearly distinct tachykinin receptors (NK,, NK, and NK, receptors, respectively) is substantiated. A correlation does not appear to exist, and there are significant mismatches between the two. For example, NK, receptors have been identified in whole brain areas and the gut plexi, but not correspondingly high neurokinin B concentrations (Than-Vinh Dam and Remi Quirion). Several chapters discuss how the successful development of selective tachykinin receptor ligands, especially antagonists, allows evaluation of potential roles for substance I’ and its congeners in peripheral function (Judith Hall), nociception (Raymond Hill) and pathology in general (Patrick Mantyh et al.). However, no disease state has yet been unequivocally demonstrated to show remission on treatment with tachykinin receptor antagonists (or agonists) even in animal models, and progress towards the original aim of developing a new class of analgesics is moving tantalizingly slowly. There are also useful chapters detailing receptor coupling to the phosphatidylinositol Ca2+-mobilizing system (James Putney) or ion channels (Yasuko Nakajima and Shigehiro Nakajima).
0
0
K
Zodiacal man. Early astrologers believed tha’ the stars Influenced the sensation of pain One of the Important a eas of mvestlgatlon of tachykmm receptor antagonists IS in analgesia. British Librarv 1
__~
This volume is not profusely illustrated, but there are some useful autoradiographic plates comparmg the distributions of the three receptor types in various tissues and species, several schemata illustrating receptor location and function, and the now familiar depictions of seven-transmembrane-receptor structures in rclation to function. Since the book went to press, there have been significant advances in our understanding of tachykinin ligand-receptor interactions gained from studies involving manoeuvres such as point mutations and deletions, and formation of chimeras. The book also misses the very recent announcement of the first relatively high-affinity NK, receptor antagonists, a development that is bound to significantly enhance our understanding of receptor function. In summary, although this book has the inevitable disadvantages of multiauthor works, including contrasting styles and overlaps and gaps in coverage, it remains unique, and in the ever-expanding area of substance P research, it is indispensable to specialists and students alike.
King’s
Ian K. M. Morton Pharmacology Group, College London, Chelsea, London, UK SW3 6LX.
TIPS
- lnnuarv
1YY5
(\‘(>I. IfI)
31
This is a substantial volume, the latest in a series on topical neurotransmitter receptors, and is arranged in nineteen chapters each by different international authorities in a particular area. It attempts, with some success, to review current understanding in this extensive and ever expanding area, and is surprisingly the first book to attempt this task, even though substance I’ was the first neuropeptide described (1931) and its receptor was the first neuropeptide receptor to be cloned (1987). The emphasis of this book is very much on receptors rather than their ligands, although there have been notable recent successes in the latter area. However, because selective receptor agonists and antagonists are still the main means of defining the properties of receptors, it is inevitable that such drugs are discussed in this context in many of the chapters. Only mammalian tachykinins and their receptors are within the remit of the book. However, over fifty tachykinins have been identified from a number of different animal families, and hence some nonmammalian peptides (for example, eledoisin, kassinin and physalaemin) and their receptors are discussed. In fact, it can be argued that some phylogenetic awareness is invaluable, since mutation and evolution can subtly alter both the signal molecule and the receptor and provide information on the essential chemical features necessary for binding of ligands and of the receptor. These earlier studies have been rapidly augmented by the various techniques of molecular biology, which are discussed primarily by James Krause rt ol. in an excellent chapter.
A recent hot topic of debate concerns heterogeneity in a given class of mammalian tachykinin receptors, either between species (proven), or within species (possible). This is an important and as yet unresolved issue in the development of drugs intended for human therapeutics from animal studies, and is the subject of an excellent and detailed chapter (Carlo Maggi). For example, in terms of the discovery of the first high-affinity nonpeptide antagonist, it is fortunate that humans are more like cows than rats in this respect, since binding to bovine brain tissue was used in the high-throughput non-rational screen used in the discovery of this ligand. It is necessary to trawl the book to determine whether the often supposed correlation between each of the three main mammalian tachykinins (substance I’, neurokinin A and neurokinin B) and the three clearly distinct tachykinin receptors (NK,, NK, and NK, receptors, respectively) is substantiated. A correlation does not appear to exist, and there are significant mismatches between the two. For example, NK, receptors have been identified in whole brain areas and the gut plexi, but not correspondingly high neurokinin B concentrations (Than-Vinh Dam and Remi Quirion). Several chapters discuss how the successful development of selective tachykinin receptor ligands, especially antagonists, allows evaluation of potential roles for substance I’ and its congeners in peripheral function (Judith Hall), nociception (Raymond Hill) and pathology in general (Patrick Mantyh et al.). However, no disease state has yet been unequivocally demonstrated to show remission on treatment with tachykinin receptor antagonists (or agonists) even in animal models, and progress towards the original aim of developing a new class of analgesics is moving tantalizingly slowly. There are also useful chapters detailing receptor coupling to the phosphatidylinositol Ca2+-mobilizing system (James Putney) or ion channels (Yasuko Nakajima and Shigehiro Nakajima).
0
0
K
Zodiacal man. Early astrologers believed tha’ the stars Influenced the sensation of pain One of the Important a eas of mvestlgatlon of tachykmm receptor antagonists IS in analgesia. British Librarv 1
__~
This volume is not profusely illustrated, but there are some useful autoradiographic plates comparmg the distributions of the three receptor types in various tissues and species, several schemata illustrating receptor location and function, and the now familiar depictions of seven-transmembrane-receptor structures in rclation to function. Since the book went to press, there have been significant advances in our understanding of tachykinin ligand-receptor interactions gained from studies involving manoeuvres such as point mutations and deletions, and formation of chimeras. The book also misses the very recent announcement of the first relatively high-affinity NK, receptor antagonists, a development that is bound to significantly enhance our understanding of receptor function. In summary, although this book has the inevitable disadvantages of multiauthor works, including contrasting styles and overlaps and gaps in coverage, it remains unique, and in the ever-expanding area of substance P research, it is indispensable to specialists and students alike.
King’s
Ian K. M. Morton Pharmacology Group, College London, Chelsea, London, UK SW3 6LX.
TIPS
- lnnuarv
1YY5
(\‘(>I. IfI)
31