Nature Vol. 295 18 February 1982 551 responses that resembles, but greatly outlasts, the response elicited by substance Fifty years of substance P P itself. The prolonged duration of action from T.M. Jessel/ of Di Me C7 in vivo provides the first indication that substance P-inactivating SUBSTANCE P, the doyen of the common agonists and analogues that are selective enzymes may in fact function physio­ peptides 1, is now 50 years old and on the for substance P receptor subtypes within logically. verge of achieving respectability as a neuro­ the central (CNS) and peripheral nervous Comparison of the potency of substance transmitter. Yet by comparison with many systems (see Table 1). By substituting P and its analogues on a battery of other peptides of inferior pedigree, the d-amino acids at residues 7 and 9, Rosell different bioassay systems is beginning to physiological functions of substance P (Karolinska Institute) and colleagues have generate a pattern of activity which may have remained obscure. Some of the synthesized a peptide analogue that reflect the existence of at least two reasons for the slow progress are easy to antagonizes the spasmogenic activity of subclasses of substance P receptors. The find. Although many of the peripheral substance P on intestinal smooth muscle clearest demonstration of this derives from actions and chemical properties were estab­ and the vasodilatory actions on peripheral studies with the tachykinins, a family of lished byvon Euler and Gaddum, it took40 vessels. At present, effective blockade of naturally occurring peptides isolated from years before substance P was eventually substance P responses can be achieved only amphibian skin, which share a common isolated and its amino acid sequence at relatively high antagonist concentrations C-terminal amino acid sequence with sub­ 5 determined. But even with the availability (10· -I0-4M) and partial agonist activity stance P 4 • For example, substance Pis five of synthetic material, advances in the has also been observed in some bioassav times more potent than the tachykinin chemistry of substance P have been disap­ systems2 • However, more potent ana kassinin as a spasmogen in the guinea pig pointingly slow. Simple modifications in specific antagonists can now be anticipated ileum, but is 100-1,000 times less active the native amino acid sequence did not im­ and their availability will undoubtedly than kassinin in potentiating the electri­ mediately generate receptor antagonists or prove crucial for evaluating many of the cally evoked contraction of the rat vas more potent agonists. More fundamental postulated physiological functions of sub­ deferens. Iversen and Hanley (MRC perhaps, the behaviour elicited by the stance P. Neurochemical Pharmacology Unit) have central or peripheral application of Attaching a methyl group to the nitrogen now extended this analysis to synthetic substance P has been less easily inter­ atom in the peptide bonds at residues 8 and substance P analogues, including the pretable than, for example, the elevation of 9 and deleting the N-terminal tetrapeptide methyl ester of substance P, which is pain threshold associated with adminis­ (Lee, Johns Hopkins Medical School) 10,000 times less active than kassinin on the tration of opioid peptides or the modi­ results in an analogue (termed Di Me C7) rat vas deferens but equipotent on the fication of feeding and drinking behaviour which is biologically active and completely guinea pig ileum5 • Iversen and Hanley have elicited by cholecystokinin and resistant to degradation by a membrane­ consequently introduced the terminology angiotensin. bound endopeptidase that inactivates SP-P and SP-E receptors to represent these At a recent CIBA Foundation substance P 3 • Whether the endopeptidase two extremes of biological activity. SP-P symposium* there were encouraging signs isolated by Lee, or any other enzyme for receptors predominate in the guinea pig that some of these obstacles have been, or which substance P can act as a substrate, is ileum and exhibit greatest selectivity for the are about to be, overcome. In particular, it actually involved in the inactivation of methyl ester of substance P and the tachy­ is now apparent that modifications of the neuronally released substance P is still kinin physalaemin. SP-E receptors are C-terminal sequence of substance P can unclear. It is conceivable that diffusion present in the rat vas deferens and are generate receptor antagonists, stable alone could effectively terminate the activated most potently by the tachykinins •CIBA Foundation Symposium no.91 'Substance P in the actions of substance P. However, injection eledoisin and kassinin. Synthetic substance Nervous System', organized by Dr Ruth Porter and chaired by Sir Arnold Burgen. was held at the CIBA Foundation 30 of Di Me C7 into the ventral tegmental area P analogues exhibiting specificity for CNS November - 3 December 1981 and followed by a one day of rats (Iversen, University of Cambridge) meeting organized by the Centre for Neuroscience at University receptors may also exist. Iversen reported College London. produces a spectrum of behavioural that extension of the C-terminal amide group produces an analogue that is ten seems probable that if a venomous snake's times more potent than substance P itself in fangs lay in its tail, it would use its teeth first displacing 3H-labelled substance P binding when attacked before bringing them into play. to rat brain membranes but has I was walking in the Botanical Gardens of only one­ Rio de Janeiro some time ago, when I found thousandth its potency on peripheral bio­ myself literally upon an immense green tree­ assay systems (Table 1). snake, at least nine or ten feet long. This The existence of mammalian receptor serpent, of course, was harmless, so that there subtypes that exhibit selectivity for 100 years ago would have been no danger in grasping it; but peptides of amphibian or arthropod origin it emitted a curious sound in its terror, such as raises the possibility NOTES ABOUT SNAKES that similar tachy­ I have never heard before or since. It kinins may also exist in mammalian A serpent's first instinctive impulse of self­ screamed, and so loudly, that some people species. In fact, Lazarus et al. have recently preservation, like that of every other animal, near, who saw nothing of what was going on, reported low lies in escape; probably a more nervous thought they heard a child cry. Serpants make amounts of physalaemin-like 6 creature does not exist. If surprised suddenly, all sorts of noises besides hissing, according to peptide in rat brain and intestine • In or brought to bay at close quarters, it may be their different kinds; Crotali spring their addition, Keen (University of Bristol) has too terror-stricken to attempt flight; then it rattles; the carpet-viper (Echis carinata) rubs observed that rat dorsal root ganglia bites, following a curious general rule which the imbricated scales of its adjacent coils incubated with 35 S-methionine can syn­ seems to obtain throughout nearly the whole together; the fer-de-lance (Trigonocephalus thesize authentic substance P and also a animal world, from a passionate child down­ /anceolatus) is said in St. Lucia to give out a peptide that is immunoprecipitated by ward, no matter what the natural weapons of series of little taps with its horny extremity; C-terminal- but not N-terminal-specific offence may be. Young Felidoe will keep their and many others - such as the rat-snake anti-substance 7 • talons sheathed until they have exterted P antisera Although the all (Spilotes variabilis) of South America - cer­ identity possible force with their soft milk-teeth, and a of this peptide is unknown, these tainly indicate their presence when angry by findings suggest that there may be a second lizard will seize the hand which restrains it with quivering their tails against the ground; but a its insignificant little jaws, when its tail or crying snake would have been a decided claws might inflict far more injury. The novelty in one's collection. Boidoe never use their constrictive powers in ARTHUR STRADLING T.M. Jessel/ is in the Department of Neuro­ self-defence (unless they arc gripped), and it From Nature 25, 16 February, 377, 1882. biology, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115. 0028-0836/ 82/ 07055 I 03 SOl.00 @ 1982 Macmillan Journals Lid .