Nothing Special   »   [go: up one dir, main page]

US3746697A - Tripeptide having the activity of the thyrotropin releasing hormone - Google Patents

Tripeptide having the activity of the thyrotropin releasing hormone Download PDF

Info

Publication number
US3746697A
US3746697A US00859559A US3746697DA US3746697A US 3746697 A US3746697 A US 3746697A US 00859559 A US00859559 A US 00859559A US 3746697D A US3746697D A US 3746697DA US 3746697 A US3746697 A US 3746697A
Authority
US
United States
Prior art keywords
tripeptide
pyro
methanol
pro
releasing hormone
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US00859559A
Inventor
K Folkers
F Enzmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Application granted granted Critical
Publication of US3746697A publication Critical patent/US3746697A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08Tripeptides
    • C07K5/0821Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • C07K5/0825Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp and Glp-amino acid; Derivatives thereof

Definitions

  • a synthetic product (pyro) glutarnyl-histidyl-proline amide having the specific and unique activities of the thyrotropin releasing hormone of the hypothalamus gland, is obtained from the tripeptide, a-glutamyl-histidylproline.
  • the tripeptide can be converted to the amide form by reacting the dimethylester with methanol and ammonia to obtain the (pyro) glutamyl-histidyl-proline amide.
  • TRH thyrotropin releasing hormone
  • the thyrotropin releasing hormone is of great value for use in the diagnostic evaluation of the functioning of the anterior pituitary gland.
  • Present medical methods employed for such evaluations have adverse etfects and produce only limited biological responses.
  • Furthermore, because the existing methods are expensive and impractical, physicians and medical researchers have been discouraged from using them.
  • a new, synthetically produced tripeptide derivative provides the same order of activity as the naturally derived thyrotropin releasing hormone obtained from mammals.
  • the newly synthesized tripeptide of the invention is especially useful because of its specificity of action for testing the function of the anterior pituitary gland. Medically, it can be used quickly, easily and accurately and diagnostic evaluation can, therefore, be performed on out-patients as Well as hospital patients.
  • the newly synthesized tripeptide of the invention can be administered to a patient intravenously, or subcutaneously and from about -30 minutes later, a blood sample can be taken from the patient and be bioassayed for the appropriate level of the pituitary hormone, particularly the thyrotropin hormone (TSH).
  • TSH thyrotropin hormone
  • the reaction is effected by dissolving the tripeptide, Glu-His-Pro (I), in anhydrous methanol containing hydrogen chloride and allowing the mixture to stand in a sealed vessel at room temperature for over an hour. The methanol and hydrogen chloride are then removed under vacuum and the residue is dissolved in anhydrous methanol containing ammonia. The reaction of the residue, the dimethylester with ammonia, takes place at room temperature in a sealed vessel over a period of several hours.
  • the resultant product, (pro) Glu-His-Pro (NH (III) is obtained by removing the excess methanol and ammonia under vacuum and subjecting it to chromatography for purification.
  • the synthetic product, (pyro), Glu-His-Pro (NI-I was subjected directly to biological testing for horomnal activity according to the methods described by C. Y. Bowers, T. W. Redding and A. V. Schally, Endocrinology, at pages 77 and 609, (1965); C. Y. Bowers, A. V. Schally, G. A. Reynolds and W. D. Hawley, Endocrinology, pages 81 and 741 (1967); and, C. Y. Bowers and A. V. Schally, Proceedings of NIH Conference on Hypothalamus, Hypophysiotropic Hormones, edited by J. Meitis, Tuscon, Arigona, in press (1969).
  • the responses were determined by the increase of the radioactive iodine I in the blood expressed as the change in the number of counts per minute (Ac.p.m.) two hours after the intravenous injection of the thyrotropin releasing hormone (TRH) and the synthetic preparation. Th'e increase of I is proportional to the amount of thyrotropin hormone (TSH) released from the pituitary gland.
  • levels of 6-54 nanograms (billionths of a gram) of the preparation in the mouse increased the level of I in the range of from about Ac.p.m. 670-8,000 as compared with from about Ac.p.m. 140170 for an acid saline solution used as control, it being understood that the amounts employed were relative as described above.
  • levels of 2, 6 and 18 nanograms of porcine TRH increased the level of the I in the range of from about Ac.p.m. 2,000-6,000.
  • the synthetic product, (pyro) Glu-His-Pro (NH was also found to be active in vitro.
  • the amount of TSH released from the pituitary into the medium was established by the level of I released from the thyroid gland of mice. Activity was measured as the level of 1 expressed as Ac.p.m., and is proportional to the amount of TSH present in the medium. It was observed that more TSH (Ac.p.m. 2300-3100) was released when 50 nanograms of the (pyro) Glu-His-Pro (NH was added to the medium than in the control (Ac.p.m. 275). It appeared that the T added in vitro or given in vivo, partially or completely inhibited the activity of the synthetic preparation.
  • EXAMPLE Commercial absolute methanol was employed but was first dried by treating it with magnesium turnings and refluxing it for 2 hours followed by distillation. Anhydrous hydrogen chloride was bubbled through the resultant anhydrous methanol until the mixture contained 5 g. of hydrogen chloride per 100 ml. of methanol (1.25 micromole/ml. hydrogen chloride).
  • the dimethylester of Glu-His-Pro hydrochloride was dissolved in 1 ml. of methanol and the mixture was transferred to a screw cap vial. The methanol was removed under vacuum and the residue was then dissolved in 2 ml. of anhydrous methanol with ammonia at -5 C. The mixture was allowed to stand at room temperature for 24 hours in the sealed screw cap vial and, after the excess methanol and ammonia were removed under vacuum at room temperature in a dessicator with sulfuric acid (pyro) Glu-His-Pro (NH was obtained.
  • pyro sulfuric acid
  • a process for preparing (pyro) glutamyl-histidylproline amide comprising; dissolving, at room temperature, a-glutamyl-histidyl-proline in anhydrous methanol containing hydrogen chloride, the molar ratio of a-glutamyl-histidyl-proline to hydrogen chloride being about 50:25; removing the methanol and hydrogen chloride under vacuum at room temperature to obtain a residue; dissolving said residue in excess anhydrous methanol; removing the solvent under vacuum at room temperature until all excess hydrogen chloride is removed to obtain the dimethylester of a-glutamyl-histidyl-proline hydrogen chloride; dissolving said dimethylester in excess methanol; removing said methanol under vacuum at room temperature to obtain a second residue; dissolving said second residue in anhydrous methanol with 2 mols ammonia at a temperature of about 5 C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

A SYTHETIC PRODUCT (PYRO) GLUTAMYL-HISTIDYL-PROLINE AMIDE, HAVING THE SPECIFIC AND UNIQUE ACTIVITIES OF THE THYROTROPIN RELEASING HORMONE OF THE HYPOTHALAMUS GLAND, IS OBTAINED FROM THE TRIPEPTIDE, A-GLUTAMYL-HISTIDYLPROLINE. THE TRIPEPTIDE CAN BE CONVERTED TO THE AMIDE FORM BY REACTING THE DIMETHYLESTER WITH METHANOL AND AMMONIA TO OBTAIN THE (PYRO) GLUTAMYL-HISTIDYL-PROLINE AMIDE.

Description

United States Patent 3,746,697 TRIPEPTIDE HAVING THE ACTIVITY OF THE THYROTROPIN RELEASING HORMONE Karl Folkers, 202 Capri-Lakeway, and Franz H. Enzmann, 1801 S. Lakeshore Blvd., both of Austin, Tex. No Drawing. Filed Sept. 19, 1969, Ser. No. 859,559 Int. Cl. C07c 103/52; C07g 7/00 U.S. Cl. 260-1125 2 Claims ABSTRACT OF THE DISCLOSURE A synthetic product (pyro) glutarnyl-histidyl-proline amide, having the specific and unique activities of the thyrotropin releasing hormone of the hypothalamus gland, is obtained from the tripeptide, a-glutamyl-histidylproline. The tripeptide can be converted to the amide form by reacting the dimethylester with methanol and ammonia to obtain the (pyro) glutamyl-histidyl-proline amide.
BACKGROUND OF THE INVENTION The thyrotropin releasing hormone (TRH) is produced by the hypothalamus gland of mammalian species, including man. It can be extracted from the glands of porcine hypothalami only by enormous effort and at great cost. For example, only 2.8 mg. of the hormone having a purity of about 30% was extracted from the glands of 100,000 pigs as has been reported by A. V. Schally, C. Y. Bowers, T. W. Redding and J. F. Barrett in Biochemistry, Biophysics Research Communications, 1966, at pages 25 and 165. Later, in 1969, only a few milligrams were again extracted from the glands of 165,- 000 pigs as reported by the above authors in the Journal of Biological Chemistry, in press (1969). Since the production of this hormone from animal glands involves great difiiculties and high expense, its extraction for general medical use is impractical.
The thyrotropin releasing hormone, however, is of great value for use in the diagnostic evaluation of the functioning of the anterior pituitary gland. Present medical methods employed for such evaluations have adverse etfects and produce only limited biological responses. Furthermore, because the existing methods are expensive and impractical, physicians and medical researchers have been discouraged from using them.
THE INVENTION It has now been discovered, in accordance with the present invention, that a new, synthetically produced tripeptide derivative provides the same order of activity as the naturally derived thyrotropin releasing hormone obtained from mammals. The newly synthesized tripeptide of the invention is especially useful because of its specificity of action for testing the function of the anterior pituitary gland. Medically, it can be used quickly, easily and accurately and diagnostic evaluation can, therefore, be performed on out-patients as Well as hospital patients. Specifically, the newly synthesized tripeptide of the invention can be administered to a patient intravenously, or subcutaneously and from about -30 minutes later, a blood sample can be taken from the patient and be bioassayed for the appropriate level of the pituitary hormone, particularly the thyrotropin hormone (TSH).
3,746,697 Patented July 17, 1973 "ice In accordance with the present invention, the tripeptide, a-glutamyl-histidyl-proline, hereinafter referred to as G1u- His-Pro, as referred to and reported by A. V. Schally, A. Arimuri, C. Y. Bowers, A. J. Kastin, S. Sarwano, T. W. Redding, Recent Progress in Hormone Research, vol. 24, p. 497, 1968, can be conveniently and easily converted to an amide form by first reacting it with methanol and hydrogen chloride to obtain the dimethylester of the tripeptide, and then reacting the dimethylester with methanol and ammonia to obtain the corresponding (pyro) g1utamyl-histidyl-proline amide, herein referred to as (pyro) Glu-His-Pro (NH These reactions can be illustrated as follows:
Glu-Hls-Pro (I) OH NH N B=J1H GH -CH H, GH -OH, C 0 H CH-C ONHH-C ON NH; CH-CH;
0 H CHaOH l H01 Dlmethylester CH Gln-His-Pro (1) NH N 6: H CIIg-GH; CH CH -GH,
(IJOZOHS JJH-C ONHCJH-C ON IL'H (EH-OH,
U OzCHa CHBOH l NH:
(pyro) Glu-Hls- CH Pro (NH (III) NH N H UH -OH, (3H CH -CH, 30 OH-CONHCH-CON NH CH- H,
0 ONE;
The reaction is effected by dissolving the tripeptide, Glu-His-Pro (I), in anhydrous methanol containing hydrogen chloride and allowing the mixture to stand in a sealed vessel at room temperature for over an hour. The methanol and hydrogen chloride are then removed under vacuum and the residue is dissolved in anhydrous methanol containing ammonia. The reaction of the residue, the dimethylester with ammonia, takes place at room temperature in a sealed vessel over a period of several hours. The resultant product, (pro) Glu-His-Pro (NH (III), is obtained by removing the excess methanol and ammonia under vacuum and subjecting it to chromatography for purification. The initial methylation of the carboxyl groups and the subsequent cyclization of the glutamic acid moiety to the lactam form and the formation of the propline were elfected by synthetic processes generally known to those skilled in the art such as those described by A. F. Beecham, Journal of American Chemical Society, at pages 76, 4615 (1954); D. Coleman, oJurnal of Chemical Society, at page 2294 (1951); and, "I. Shiba, S. Imai, and Kameko, Bulletin of a 3 Chemical Society, Japan, at pages 42 and 244, (1958).
At the time the discovery of the synthetic tripeptide derivative of the invention was made, the structure of thyrotropin releasing hormone was not known, since only limited amounts have been extracted and made available for analysis, and since the extracted, natural homone has a purity of only about 30%. Consequently, it was entirely unpredictable that a hormonally inactive tripeptide would be converted by these reactions of methylation and ammonation to a new product having a hormonal activity indistinguishable from that of the naturally occurring thyrotropin releasing hormone of the hypothalamus.
The synthetic product, (pyro), Glu-His-Pro (NI-I was subjected directly to biological testing for horomnal activity according to the methods described by C. Y. Bowers, T. W. Redding and A. V. Schally, Endocrinology, at pages 77 and 609, (1965); C. Y. Bowers, A. V. Schally, G. A. Reynolds and W. D. Hawley, Endocrinology, pages 81 and 741 (1967); and, C. Y. Bowers and A. V. Schally, Proceedings of NIH Conference on Hypothalamus, Hypophysiotropic Hormones, edited by J. Meitis, Tuscon, Arigona, in press (1969). The responses were determined by the increase of the radioactive iodine I in the blood expressed as the change in the number of counts per minute (Ac.p.m.) two hours after the intravenous injection of the thyrotropin releasing hormone (TRH) and the synthetic preparation. Th'e increase of I is proportional to the amount of thyrotropin hormone (TSH) released from the pituitary gland.
Since the doses of the synthetic preparation represent the weights of the starting material, they are the relative rather than the actual amounts of the synthetic product given. Although the synthetic product was visualized chromatographically its yield was not established.
For example, when tested in a mouse, levels of 6-54 nanograms (billionths of a gram) of the preparation in the mouse increased the level of I in the range of from about Ac.p.m. 670-8,000 as compared with from about Ac.p.m. 140170 for an acid saline solution used as control, it being understood that the amounts employed were relative as described above. On the other hand, levels of 2, 6 and 18 nanograms of porcine TRH increased the level of the I in the range of from about Ac.p.m. 2,000-6,000.
It is significant to note that the synthetic preparation was extremely active in comparison with porcine TRH. Graded responses were obtained when the dosage of the synthetic preparation was increased, and two of the important biological characteristics of natural TRH were observed; viz, (a) the degree of response depended upon the amount of triiodothyronine (T injected; and, (b) incubation of the preparation for minutes at 37 C. in normal human blood plasma inactivated the synthetic preparation.
The synthetic product, (pyro) Glu-His-Pro (NH was also found to be active in vitro. The amount of TSH released from the pituitary into the medium was established by the level of I released from the thyroid gland of mice. Activity was measured as the level of 1 expressed as Ac.p.m., and is proportional to the amount of TSH present in the medium. It was observed that more TSH (Ac.p.m. 2300-3100) was released when 50 nanograms of the (pyro) Glu-His-Pro (NH was added to the medium than in the control (Ac.p.m. 275). It appeared that the T added in vitro or given in vivo, partially or completely inhibited the activity of the synthetic preparation.
A comparison was made of the changes in blood levels of I in mice at various time intervals after intravenous injections of (1) an acid saline control solution, (2) the synthetic (pyro) Glu-His-Pro (NH and (3) porcine and bovine TRH. It was observed that the time-response curves of the active compounds were essentially the same,
but that there was a definite rise after a 60 minute interval, and the levels were even higher at minutes and remained elevated at and minutes.
In the other tests, it was found that the (pyro) Glu- His-Pro (NH elevated the plasma levels of TSH in rats and produced an increase in plasma levels of TSH Within 2 minutes after being intravenously injected into mice. The plasma levels of TSH were observed to be highest at the 10 and 15 minute intervals and remained elevated for 60 minutes, but started to fall at the 120 minute interval. The (pyro) Glu-His-Pro (NH was found to be active in mice whether given intravenously or intraperitoneally.
The following example is set forth to illustrate one method of synthesizing the (pyro) Glu-His-Pro (NHQ).
of the present invention.
EXAMPLE Commercial absolute methanol was employed but was first dried by treating it with magnesium turnings and refluxing it for 2 hours followed by distillation. Anhydrous hydrogen chloride was bubbled through the resultant anhydrous methanol until the mixture contained 5 g. of hydrogen chloride per 100 ml. of methanol (1.25 micromole/ml. hydrogen chloride).
Two milligrams of u-Glu-His-Pro (I) (5 micromoles) was then dissolved in 2 ml. of the anhydrous methanol containing the 1.25 micromole/ ml. hydrogen chloride and the mixture was allowed to stand in a sealed screw cap vial at room temperature for 90 minutes. The methanol and hydrogen chloride were then removed at room temperature under vacuum and over sodium hydroxide in a dessicator. The residue was dissolved in anhydrous methanol and the solvent was removed under vacuum. This residue was then redissolved in anhydrous methanol and the solvent was removed under vacuum several times in order to remove the excess hydrogen chloride.
Next, the dimethylester of Glu-His-Pro hydrochloride was dissolved in 1 ml. of methanol and the mixture was transferred to a screw cap vial. The methanol was removed under vacuum and the residue was then dissolved in 2 ml. of anhydrous methanol with ammonia at -5 C. The mixture was allowed to stand at room temperature for 24 hours in the sealed screw cap vial and, after the excess methanol and ammonia were removed under vacuum at room temperature in a dessicator with sulfuric acid (pyro) Glu-His-Pro (NH was obtained.
The new product (pyro) Glu-His-Pro (NI-I exhibited a positive reaction with the Pauly reageant revealing the presence of the NH group of the histidine moiety. It also exhibited no reaction with the ninhydrin reagent indicating that the amino group of the glutamic acid moiety is cyclized to the lactam form.
In the table set forth below (Table I), there is listed the data obtained for the chromatographic (R,) values from 4 diversified chromatographic solvent systems, each of which involved diiferent commercially available adsorbents and which reveal the chemical mobility and nature of the novel product of the invention. In Table I, the ratios of components in the solvent systems are by volume and the adsorbents are identified by their commercial trademarks.
What is claimed:
'1. A synthetic tripeptide of substantially 100% purity (pyro) glutamyl-histidyl-proline amide, having the structure said synthetic tripeptide having the same hormonal activity as the naturally derived thyrotropin releasing hormone of the hypothalamus gland of mammalian species.
2. A process for preparing (pyro) glutamyl-histidylproline amide, comprising; dissolving, at room temperature, a-glutamyl-histidyl-proline in anhydrous methanol containing hydrogen chloride, the molar ratio of a-glutamyl-histidyl-proline to hydrogen chloride being about 50:25; removing the methanol and hydrogen chloride under vacuum at room temperature to obtain a residue; dissolving said residue in excess anhydrous methanol; removing the solvent under vacuum at room temperature until all excess hydrogen chloride is removed to obtain the dimethylester of a-glutamyl-histidyl-proline hydrogen chloride; dissolving said dimethylester in excess methanol; removing said methanol under vacuum at room temperature to obtain a second residue; dissolving said second residue in anhydrous methanol with 2 mols ammonia at a temperature of about 5 C. to obtain a mixture; sealing said mixture from the atmosphere and permitting it to stand at room temperature for a period of about 24 hours; and, removing excess methanol and ammonia under vacuum at room temperature from said mixture to obtain (pyro) glutamyl-histidyl-proline amide.
References Cited UNITED STATES PATENTS 3,076,797 2/ 1963 Velluz et a1. 260-1125 3,250,759 5/196-6 Bodanszky et a1. 260-112.5
FOREIGN PATENTS 1,331,765 5/ 1963 France 2'60l12.5
OTHER REFERENCES Burgus et al.: C. R. Acad. Sci., Paris, Ser. D, 268, 2116-2118 (1969).
Burgus et al.: C. R. Acad. Sci., Paris, Ser. D, 269, 226- 228 (1969).
Guillemin: Pharmacology of Hormonal Polypeptides and Proteins, Bach et al., ed., Plenum Press, New York (1968), pp. 148-157.
Schally et al.: Biochem. Biophys. Res. Commun. 25, 169 (1966).
Schally et al.: Recent Progress Hormone Research 24, 510-525 (1968).
Shiba et al.: Bull. Chem. Soc., Japan, 31, 244-245 (1958).
Schroder et al.: The Peptides, vol. I, Academic Press, New York (1965), PP- 193-194.
Beecham: J. Amer. Chem. Soc., 76, 4615 (1954).
Folkers et al.: Biochem. Biophys. Res. Commun., 37, 123-126 (1969).
Schmeck: New York Times, vol. CXIX, No. 40,895, Jan. 11, 1970, Sec. 1, pages 1 and 40.
ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R. 260l12.5
US00859559A 1969-09-19 1969-09-19 Tripeptide having the activity of the thyrotropin releasing hormone Expired - Lifetime US3746697A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US85955969A 1969-09-19 1969-09-19

Publications (1)

Publication Number Publication Date
US3746697A true US3746697A (en) 1973-07-17

Family

ID=25331203

Family Applications (1)

Application Number Title Priority Date Filing Date
US00859559A Expired - Lifetime US3746697A (en) 1969-09-19 1969-09-19 Tripeptide having the activity of the thyrotropin releasing hormone

Country Status (2)

Country Link
US (1) US3746697A (en)
AU (1) AU2018870A (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3860570A (en) * 1973-02-26 1975-01-14 Abbott Lab Tripeptide intermediate for making trh
US3862926A (en) * 1970-08-06 1975-01-28 Abbott Lab Simplified method for the manufacture of the thyrotropin release hormone
US4150120A (en) * 1977-01-05 1979-04-17 Takeda Chemical Industries, Ltd. Ophthalmic
US4426378A (en) 1981-04-09 1984-01-17 The United States Of America As Represented By The Secretary Of The Army Thyrotropin releasing hormone in therapy of shock and as a central nervous system stimulant
US4493828A (en) * 1982-07-26 1985-01-15 Merck & Co., Inc. Use of thyrotropin releasing hormone and related peptides as poultry growth promotants
US4608365A (en) * 1984-03-30 1986-08-26 University Of Southern California Treatment of neurologic functions
US5830866A (en) * 1994-09-12 1998-11-03 The Trustees Of The University Of Pennsylvania Corticotropin release inhibiting factor and methods of using same
US6039956A (en) * 1994-09-12 2000-03-21 Pennsylvania, Trustees Of The University Of, The Corticotropin release inhibiting factor and methods of using same for treating behavioral symptoms in an anxiety disorder
US20030185755A1 (en) * 1995-10-06 2003-10-02 Heska Corporation. Novel ectoparasite saliva proteins and apparatus to collect such proteins

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3862926A (en) * 1970-08-06 1975-01-28 Abbott Lab Simplified method for the manufacture of the thyrotropin release hormone
US3860570A (en) * 1973-02-26 1975-01-14 Abbott Lab Tripeptide intermediate for making trh
US4150120A (en) * 1977-01-05 1979-04-17 Takeda Chemical Industries, Ltd. Ophthalmic
US4426378A (en) 1981-04-09 1984-01-17 The United States Of America As Represented By The Secretary Of The Army Thyrotropin releasing hormone in therapy of shock and as a central nervous system stimulant
US4493828A (en) * 1982-07-26 1985-01-15 Merck & Co., Inc. Use of thyrotropin releasing hormone and related peptides as poultry growth promotants
US4608365A (en) * 1984-03-30 1986-08-26 University Of Southern California Treatment of neurologic functions
US5830866A (en) * 1994-09-12 1998-11-03 The Trustees Of The University Of Pennsylvania Corticotropin release inhibiting factor and methods of using same
US6039956A (en) * 1994-09-12 2000-03-21 Pennsylvania, Trustees Of The University Of, The Corticotropin release inhibiting factor and methods of using same for treating behavioral symptoms in an anxiety disorder
US20070154920A1 (en) * 1994-10-07 2007-07-05 Heska Corporation Novel Ectoparasite Saliva Proteins
US7629446B2 (en) 1994-10-07 2009-12-08 Heska Corporation Nucleic acid molecules encoding a novel ectoparasite saliva protein
US20030185755A1 (en) * 1995-10-06 2003-10-02 Heska Corporation. Novel ectoparasite saliva proteins and apparatus to collect such proteins
US7166693B2 (en) 1995-10-06 2007-01-23 Heska Corporation Ectoparasite saliva proteins

Also Published As

Publication number Publication date
AU2018870A (en) 1972-03-23

Similar Documents

Publication Publication Date Title
Manning et al. Solid-phase synthesis of [4-threonine]-oxytocin. More potent and specific oxytocic agent than oxytocin
Pelton et al. Conformationally restricted analogs of somatostatin with high mu-opiate receptor specificity.
Bowers et al. Porcine thyrotropin releasing hormone is (pyro) glu-his-pro (NH2)
Veber et al. Conformationally restricted bicyclic analogs of somatostatin.
Meyers et al. Highly active position eight analogs of somatostatin and separation of peptide diastereomers by partition chromatography
US3746697A (en) Tripeptide having the activity of the thyrotropin releasing hormone
PAPKOFF et al. Studies on the structure and function of interstitial cell-stimulating hormone
CA2210664A1 (en) Calcitonin salmon analogues, their preparation, medicinal use and use as analytical agents
YANG et al. Iodination of ovine luteinizing hormone and its subunits
FUJINO et al. Synthesis of the nonacosapeptide corresponding to mammalian glucagon
US4010149A (en) Analogs of LH-RH and process for preparing the same
Baugh et al. Synthesis and biological activity of thyrotropin-releasing hormone
Papaionannou et al. Comparison of the binding of human chorionic gonadotropin to isolated bovine luteal cells and bovine luteal plasma membranes
Bowers et al. Activity-structure relationships of the thyrotropin releasing hormone
Yanaihara et al. Syntheses and biological evaluation of analogs of luteinizing hormone-releasing hormone (LH-RH) modified in position 2, 3, 4 or 5
JPH0224838B2 (en)
US3753969A (en) Method for synthesizing pyroglutamylhistidyl-prolinamide
Folkers et al. Structure and synthesis of the thyrotropin-releasing hormone
Yanaihara et al. Syntheses and biological activities of analogs of luteinizing hormone-releasing hormone (LH-RH) substituted in position 1 or 2
US4280953A (en) Glycosylated analogs of somatostatin
Li et al. The synthesis of L-histidyl-L-phenylalanyl-L-ornithyl-L-tryptophyl-glycine and L-histidyl-D-phenylalanyl-L-ornithyl-L-tryptophyl-glycine and their melanocyte-stimulating activity
Sievertsson et al. Hypothalamic hormones. 35. Two syntheses of the luteinizing hormone releasing hormone of the hypothalamus
Arnold et al. Synthesis and biological activity of some analogs of the gonadotropin releasing hormone
Prasad et al. Structure-activity relationships in luteinizing hormone-releasing hormone
Hofmann et al. STUDIES ON POLYPEPTIDES. XII THE SYNTHESIS OF A PHYSIOLOGICALLY ACTIVE BLOCKED TRIDECAPEPTIDE AMIDE POSSESSING THE AMINO ACID SEQUENCE OF α-MSH1