The present invention relates to new polypeptides which have pronounced antagonistic properties towards substance P, a process for their preparation, their use in combating diseases, and pharmaceutical products containing them. The invention furthermore relates to an advantageous process for the purification of polypeptides.
Euler and Gaddum ((1931), J. Physiol. (London) 72 74-87) were the first to describe a biological activity from tissue extracts which had a contraction-stimulating action on the jejunum of guinea pigs and a dilating action on the blood vessels in rabbits. They called the activity "substance P", but needless to say were not able to isolate the compound responsible in a pure form. This was only achieved later, when Leeman and Hammerschlag 1967 (Endocrinology 81, 803-810) discovered the salivant action of a hypothalamus fraction. As a result of this simple detection system, the study group was able to obtain the active principle in a homogeneous form (Chang & Leeman 1979, J. Biol. Chem. 245, 4784-4790). It was a peptide of the following structure: EQU Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH.sub.2
This peptide was soon identified as substance P, since it had the same properties as the fractions partly purified by Euler and Gaddum. As the peptide was now accessible by synthesis (the first synthesis was described by Tregear et al. (1974, Nature (London) 232, 87-89), it was also possible to develop a specific radioimmunoassay for the peptide. This enabled the distribution of the substance in various tissues to be determined, and thus considerably stimulated research into substance P.
Substance P was detected in a large number of different tissues and cellular structures. Since this detection in most cases was by radioimmunological methods, the literature refers to ISP (immunoreactive substance P). Organs in which ISP occurs are: mammalian intestine, salivary gland, trachea, pancreas, kidney, bladder, prostate gland, substantia nigra, hypothalamus, pineal gland and dorsal horn.
ISP is evidently localized in nerves belonging to the autonomic nervous system and primary sensory nerve fibers (for example fibers responsible for referring pain). ISP has been found in the plexus myentericus (Auerbach's plexus) and in diffuse nerve fibers between the smooth muscle cells of the small intestine. ISP also occurs in endocrinal cells in the mucous membrane of the intestine.
An inhibitor which specifically blocks the action of the peptide would be of great advantage in the research into the biological functions of substance P.
Recently, specific and competitive inhibitors have been successfully synthesized. These are substances in which the aminoacids in positions 2, 7 and 9 are replaced by other aminoacids. D-Pro.sup.2, D-Phe.sup.7 and D-Trp-.sup.9 -SP (Folkers et al. (1981) Acta Physiol. Scand. 111, 505-506; and Rosell et al. (1981) Acta Physiol. Scand. 111, 381-382) inhibit the contraction of the ileum in guinea pigs caused by SP, SP-induced salivation and vasodilation caused by antidromic nerve stimulation and SP-induced vasodilation.
USPTO Backgrounds
USPTO Backgrounds