Synthesis of new potent agonistic analogs of growth hormone-releasing hormone (GHRH) and evaluation of their endocrine and cardiac activities

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2014-02, Vol.52, p.104-112
• Main Authors: Cai, Renzhi, Schally, Andrew V., Cui, Tengjiao, Szalontay, Luca, Halmos, Gabor, Sha, Wei, Kovacs, Magdolna, Jaszberenyi, Miklos, He, Jinlin, Rick, Ferenc G., Popovics, Petra, Kanashiro-Takeuchi, Rosemeire, Hare, Joshua M., Block, Norman L., Zarandi, Marta
• Format: Article
• Language: English
• Subjects: Agmatine; agonists; Analogs; Animals; Binding; Biological effects; cardiomyocytes; Cardioprotection; diabetes; Endocrine System - metabolism; Growth Hormone-Releasing Hormone - agonists; Growth Hormone-Releasing Hormone - metabolism; hGHRH agonist; hGHRH(1–29); In vitro testing; islets of Langerhans; Medical; myocardial infarction; Peptides; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Protein Structure, Secondary; Rats; Rats, Sprague-Dawley; s.c. administration; somatoliberin; Structure-Activity Relationship; subcutaneous injection; Surgical implants; Wound healing
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2013.12.010

•Analogs of GHRH modified at the N- and/or C-terminus were designed and synthesized.•Endocrine activities and binding affinities were determined.•Two analogs highly activated myocardial repair after induced myocardial infarction.•The relationship between GH-releasing potency and structure is discussed.•Substitutions with N-Me-Tyr1, Arg30-NHCH3, or Apa30-NH2 increased GHRH activities. In view of the recent findings of stimulatory effects of GHRH analogs, JI-34, JI-36 and JI-38, on cardiomyocytes, pancreatic islets and wound healing, three series of new analogs of GHRH(1–29) have been synthesized and evaluated biologically in an endeavor to produce more potent compounds. “Agmatine analogs”, MR-356 (N-Me-Tyr1-JI-38), MR-361(N-Me-Tyr1, D-Ala2-JI-38) and MR-367(N-Me-Tyr1, D-Ala2, Asn8-JI-38), in which Dat in JI-38 is replaced by N-Me-Tyr1, showed improved relative potencies on GH release upon subcutaneous administration in vivo and binding in vitro. Modification with N-Me-Tyr1 and Arg29-NHCH3 as in MR-403 (N-Me-Tyr1, D-Ala2, Arg29-NHCH3-JI-38), MR-406 (N-Me-Tyr1, Arg29-NHCH3-JI-38) and MR-409 (N-Me-Tyr1, D-Ala2, Asn8, Arg29-NHCH3-JI-38), and MR-410 (N-Me-Tyr1, D-Ala2, Thr8, Arg29-NHCH3-JI-38) resulted in dramatically increased endocrine activities. These appear to be the most potent GHRH agonistic analogs so far developed. Analogs with Apa30-NH2 such as MR-326 (N-Me-Tyr1, D-Ala2, Arg29, Apa30-NH2-JI-38), and with Gab30-NH2, as MR-502 (D-Ala2, 5F-Phe6, Ser28, Arg29,Gab30-NH2-JI-38) also exhibited much higher potency than JI-38 upon i.v. administration. The relationship between the GH-releasing potency and the analog structure is discussed. Fourteen GHRH agonists with the highest endocrine potencies were subjected to cardiologic tests. MR-409 and MR-356 exhibited higher potency than JI-38 in activating myocardial repair in rats with induced myocardial infarction. As the previous class of analogs, exemplified by JI-38, had shown promising results in multiple fields including cardiology, diabetes and wound healing, our new, more potent, GHRH agonists should manifest additional efficacy for possible medical applications.