Substance P

Literature References: An undecapeptide belonging to a group of proteins named tachykinins characterized by contractile action on extravascular smooth muscle. Discovered by von Euler and Gaddum, J. Physiol. 72, 74 (1931). Present in the brain of all vertebrates including man, in spinal ganglia, and in the intestines, esp the duodenum and jejunum. Isoln from cattle brain: Zuber, Jaques, Angew. Chem. Int. Ed. 1, 160 (1962); from horse intestine: Studer et al., Helv. Chim. Acta 56, 860 (1973). Purification from bovine hypothalami and amino acid composition: N. N. Chang, S. E. Leeman, J. Biol. Chem. 245, 4784 (1970). Amino acid sequence and solid-phase synthesis: Chang et al., Nature New Biol. 232, 86 (1971); Tregear et al., ibid. 87; G. H. Fisher et al., J. Med. Chem. 17, 843 (1974). Additional syntheses: Yajima, Kitigawa, Chem. Pharm. Bull. 21, 682 (1973); Bayer, Mutter, Ber. 107, 1344 (1974); K. Neubert et al., Pharmazie 36, 10 (1981); A. Fournier et al., J. Med. Chem. 25, 64 (1981). Substance P acts as a vasodilator, a depressant, stimulates salivation and produces increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on dose and pain responsiveness of the animal, see R. C. A. Frederickson et al., Science 199, 1359 (1978); P. Oehme et al., ibid. 208, 305 (1980); role in sensory transmission and pain perception: T. M. Jessell, Adv. Biochem. Psychopharmacol. 28, 189 (1981). Mechanism of action studies: Stern et al., Arch. Pharmacol. 281, 233 (1974); B. G. Livett et al., Nature 278, 256 (1979). Reviews: Haefeli, Huelimann, Experientia 18, 297 (1962); Lembeck, Zetler in International Encyclopedia of Pharmacology and Therapeutics sect. 72, vol. 1, J. M. Walker, Ed. (Pergamon Press, New York, 1971) pp 29-71; J. L. Barker, Physiol. Rev. 56, 435 (1976); D. R. Brown, R. J. Miller, Annu. Rep. Med. Chem. 17, 271-280 (1982). Books: U.S. Von Euler, B. Pernow, Eds., Substance P (Raven Press, New York, 1977) 360 pp; Substance P vol. 2, P. Skrabanek, D. Powell, Eds. (Eden Press, Quebec, 1980) 175 pp; Substance P in The Nervous System: Ciba Foundation Symposium 91, R. Porter, M. O'Connor, Eds. (Pitman, London, 1982) 350 pp.

Properties: Behaves during isoln as a basic polypeptide (Rf value = 0.5 in the thin layer chromatogram: silica gel n-butanol/pyridine/AcOH/H2O = 30:20:6:24). Upon high voltage electrophoresis (pH 1.9; acetic acid/formic acid/H2O = 15:3:100) it migrates approx as far as glutamic acid or serine, and at pH 9.5 (0.25M triethylammonium carbonate buffer) it behaves in a manner similar to arginine. Biological activity is destroyed by pepsin and chymotrypsin. Aqueous solns of highly purified material lose biological activity in a few minutes. This loss is prevented by storage at low pH, under nitrogen, or with various antioxidants. Addition of Tween 80, gelatin, human plasma albumin, or bovine g-globulin increases stability of aq SP solns. Crude SP solns are stable though rapidly destroyed above pH 8.