Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-05-02
1999-01-12
Chan, Christina Y.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 21, 514866, 530308, 530324, A61K 3823, C07K 504
Patent
active
058589759
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP95/02269, filed Nov. 7, 1995.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel peptide or Pharmaceutically acceptable salts thereof, which have cardiotonic activity and insulin release-promoting activity and are useful for prevention or treatment of cardiopathy or diabetes.
BRIEF DESCRIPTION OF THE BACKGROUND ART
Oxyntomodulin (hereinafter referred to as OXM) is a peptide which is produced by post-translational processing of proglucagon, like glucagon (peptide composed of 29 amino acids), glucagon-like peptides and glicentin, and is recognized to exist in intestines and hypothalamus. OXM has a structure of glucagon or glucagon-like peptide to which are added 7 or 8 amino acid residues at its carboxyl terminal, and its structures in porcine (D. Bataille et al., FEBS Lett., 146, 73-78, 1982), in bovine (J. M. Conlon et al., Regul. Pept., 11, 309-320, 1985), in rat (A. Kervran et al., Endocrinol., 121, 704-713, 1987), in shark (J. M.
Conlon et al., Biochem. J., 245, 851-855, 1987), in canine (Y. Shinomura et al., Regul. Pept., 23, 299-308, 1988), in bullfrog (H. G. Pollock et al., J. Biol. Chem., 263, 9746-9751, 1988), and in alligator (H. G. Pollock et al., Gen.
Comp. Endocrinol., 69, 133-140, 1988) have been clarified at present. The primary structures of OXM of every species are similar to each other, having neither cysteine residue nor proline residue in the molecule. Regarding the physiological activities of OXM, for example, its somatostatin secretion-promoting activity (T. Tani et al., Biochim. Biophys. Acta, 1095, 249-254, 1991), its gastric acid secretion-inhibiting activity (T. M. Biedzinski et al., Peptides, 8, 967-972, 1987), and its insulin secretion-promoting activity (C. Jarrousse et al., Endocrinol., 115, 102-105, 1984) have heretofore been reported. It is believed that OXM may exhibit its physiological functions via a receptor which is different from that for glucagon (C. Depigny et al., C.R. Acad. Sci. III (France), 299, 677-680, 1984). However, this belief has not been completely clarified as yet. Though being similar to glucagon in its primary structure, OXM obviously differs from glucagon, for example, in its distribution in tissue and its gastric acid secretion-inhibiting activity. To further clarify the physiological activities of OXM, the analysis of its structures in further lower animals is also important. For example, regarding the effect of calcitonin on calcium concentration on the rat plasma, it is known that the effect of eel calcitonin is obviously higher than those of rat, porcine and human calcitonins (M. Otani et al., J. Biochem., 79, 345-352, 1976; M. Azria, Prog. Clin. Biochem. Med., 9, 1-33, 1989). However, the presence of eel OXM, the structure thereof and the physiological activities thereof are not known up to these days.
SUMMARY OF THE INVENTION
We, the present inventors have variously studied substances existing in eel intestines, and as a result, have found a novel factor having atrial contractile activity. As a result of having further studied it, we have found that this factor is a novel peptide, while having a cardiotonic activity and an insulin release-promoting activity, and is therefore useful as a medicine for cardiopathy, diabetes, etc. On the basis of these findings, we have completed the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the effect of Oxyntomodulin on eel atrial systole;
FIG. 2 shows the effect of Oxyntomodulin on eel atrial rate; and
FIG. 3 shows the effect of Oxyntomodulin on rat plasma insulin concentration.
DETAILED DESCRIPTION OF THE INVENTION
Specifically, the present invention relates to a peptide of the following formula (I):
H-His-Ser-Gln-Gly-Thr-Phe-Thr-Asn-Asp-Tyr-Ser-Lys-Tyr-Leu-Glu-Thr-Arg-Arg-A la-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Ser-Lys-Arg-Ser-Gly-Gly-Pro-Thr-OH (SEQ ID NO:1)(I) or pharmaceutically acceptable salts thereof.
The abbreviations for the corresponding amino acids in formula (I) are generally used in
REFERENCES:
Conlon et al., Gen. & Comp. Endocrinology, vol. 72 (1988) 181-189.
Bataille et al., FEBS Letters, vol. 146, No. 1 (Sep. 1982) 73-78.
Conlon et al., Regulatory Peptides, vol. 11 (1985) 309-320.
Kervran et al., Endocrinology, vol. 121, No. 1 (1987) 704-713.
Conlon et al., Biochem. J., vol. 245 (1987) 851-855.
Shinomura et al., Regulatory Peptids, vol. 23 (1988) 299-308.
Pollock et al., Journal of Biol. Chem., vol. 263, No. 20 (1988) 9746-51.
Pollock et al., Gen. & Comp. Endocrinology, vol. 69 (1988) 133-140.
Tanbi et al., Biochimica et Biophysica Acta, vol. 1095 (1991) 249-254.
Biedzinski et al., Peptides, vol. 8 (1987) 967-972.
Jarrousse et al., Endocrinology, vol. 115, No. 1, (1984) 102-105.
Depigny et al., C.R. Acad. Sc., Paris, vol. III, No. 16 (1984) 677-680.
Otani et al., J. Biochem., vol. 79, No. 2 (1976) 345-352.
Azria et al., Progress in Clin. Biochem. & Med., vol. 9, Calcitonins, 1-34 (1989).
Bataille et al., FEBS Letters, vol. 146, No. 1 (1982) 79-87.
Gros et al., Eur. Journal. Pharm., Mol. Pharm. Sec. 288 (1995) 319-327.
Gros et al., Endocrinology, vol. 130, No. 3 (1992) 1263-1270.
Collie et al., Proc. Natl. Acad. Sci., vol. 91 (Sep. 1994) 9362-9366.
Nathan et al., Diabetes Care, vol. 15, No. 2 (Feb. 1992) 270-276.
Ando Masaaki
Moriyama Takahiro
Yamasaki Motoo
Yano Keiichi
Chan Christina Y.
Kyowa Hakko Kogyo Co. Ltd.
Tung Mary Beth
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