Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1984-04-04
1985-08-06
Phillips, Delbert R.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 13, 2601125R, A61K 3700, C07C10352
Patent
active
045336547
DESCRIPTION:
BRIEF SUMMARY
This invention is directed to peptides related to Urotensin I (UI) from carp and to methods for pharmaceutical treatment of mammals using such peptides. More specifically, the invention relates to UI and fragments of UI, to pharmaceutical compositions containing UI or fragments thereof, and to methods of treatment of mammals using such compositions.
BACKGROUND OF THE INVENTION
Experimental and clinical observations have supported the concept that the hypothalamus plays a key role in the regulation of adenohypophysial corticotropic cells' secretory functions. Over 25 years ago, Guillemin, Rosenberg and Saffran and Schally independently demonstrated the presence of factors in hypothalamus which would increase the rate of ACTH secretion by the pituitary gland incubated in vitro or maintained in an organ culture. A physiologic corticotrop regulatory factor, CRF, was extracted from sheep hypothalamic fragments and characterized and synthesized by the Peptide Biology Laboratory at The Salk Institute, as described in Vale et al., Science 213: 1394-1397, 1981.
Sauvagine is a 40-residue, amidated generally similar peptide, which was isolated from the skin of the South American frog Phyllomedusa sauvagei and which was characterized by Erspamer et al. and described in Regulatory Peptides, Vol. 2 (1981), pp. 1-13. Sauvagine has the formula: pGlu-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-Glu-Leu-Leu-Arg-Lys-Met-Ile-G lu-Ile-Glu-Lys-Gln-Glu-Lys-Glu-Lys-Gln-Gln-Ala-Ala-Asn-Asn-Arg-Leu-Leu-Leu- Asp-Thr-Ile-NH.sub.2. Sauvagine has been reported to have biological activity in lowering blood pressure in mammals and in stimulating the secretion of ACTH and .beta.-endorphin.
SUMMARY OF THE INVENTION
UI from Cyprinus carpio has now been isolated, purified, characterized and synthesized. It is a polypeptide having the formula: H-Asn-Asp-Asp-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Asn-Met- Ile-Glu-Met-Ala-Arg-Asn-Glu-Asn-Gln-Arg-Glu-Gln-Ala-Gly-Leu-Asn-Arg-Lys-Tyr -Leu-Asp-Glu-Val-NH.sub.2, and may alternatively be referred to as carp urotensin. UI has been found to stimulate ACTH and .beta.-endorphin activities in vitro and in vivo and to lower blood pressure for an extended time period. UI in substantially pure form (i.e. substantially free of the remainder of a crude biological extract or of related synthetic replicates) can be employed in pharmaceutical compositions, and a purity of at least about 93% or higher (based upon other peptides present) is practically obtainable and preferred for clinical testing.
The fragment of carp urotensin (UI 4-41) having the following formula: H-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Asn-Met-Ile-Glu-Met- Ala-Arg-Asn-Glu-Asn-Gln-Arg-Glu-Gln-Ala-Gly-Leu-Asn-Arg-Lys-Tyr-Leu-Asp-Glu -Val-NH.sub.2 has substantially the same biological activity as the 41-residue polypeptide.
Pharmaceutical compositions in accordance with the invention include synthetic UI or its fragments, or nontoxic addition salts thereof, dispersed in a pharmaceutically acceptable liquid or solid carrier. The administration of such peptides or pharmaceutically acceptable addition salts thereof to mammals in accordance with the invention may be carried out for the regulation of secretion of ACTH, .beta.-endorphin, .beta.-lipotropin, and corticosterone and/or for the long-lasting lowering of systemic blood pressure and related cardiovascular effects.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
UI was isolated from carp urophysis extracts, purified and characterized; urophyses are the hormone storage-release organs of the caudal neurosecretory system. The nomenclature used to define the peptides is that specified by Schroder and Lubke, "The Peptides", Academic Press (1965) wherein, in accordance with conventional representation, the N-terminal appears to the left and the C-terminal to the right. Where the amino acid residue has isomeric forms, it is the L-form of the amino acid that is represented.
Such invention provides UI having the following formula: H-Asn-Asp-Asp-Pro-Pro-Ile-Ser-Ile-Asp-Le
REFERENCES:
patent: 4385050 (1983-05-01), Lederis et al.
Program and Abstracts, Jun. 1982, Meeting of the Endocrine Society--Abstract No. 756 (p. 268).
Rivier et al., Biopolymers 17, (1978), 1927-1938.
Gerriston et al., European Journal of Pharmacology 60, (1979), 211-220.
Akaji et al., Chem. Pharmacology Bulletin 30, 349-353 (1982).
Kapoor, Journal of Pharmaceutical Science 59, (1970), 1-27.
Clark et al., Biol. Abstr. 74, (1982), 70624.
Vale et al., Science 213, (1981), 1394-1397.
Atherton et al., Bioorganic Chem. 8, (1979), 351-370.
Melchorri et al., Regulatory Peptides 2, (1981), 1-13.
Schroeder et al., The Peptides 1, (1965), 72-75.
Merrifield, Solid Phase Peptide Synthesis (1963), 2149-2154.
Ichikawa Tomoyuki
Lederis Karl P.
MacCannell Keith L.
Phillips Delbert R.
The Salk Institute for Biological Studies
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