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

Renzhi Cai, Andrew V Schally, Tengjiao Cui, Luca Szalontay, Gabor Halmos, Wei Sha, Magdolna Kovacs, Miklos Jaszberenyi, Jinlin He, Ferenc G. Rick, Petra Popovics, Rosemeire Takeuchi, Joshua Hare, Norman L Block, Marta Zarandi

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Abstract

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-Tyr 1, showed improved relative potencies on GH release upon subcutaneous administration in vivo and binding in vitro. Modification with N-Me-Tyr 1 and Arg29-NHCH3 as in MR-403 (N-Me-Tyr 1, D-Ala2, Arg29-NHCH3-JI-38), MR-406 (N-Me-Tyr1, Arg29-NHCH3-JI-38) and MR-409 (N-Me-Tyr1, D-Ala2, Asn8, Arg 29-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 Apa 30-NH2 such as MR-326 (N-Me-Tyr1, D-Ala 2, Arg29, Apa30-NH2-JI-38), and with Gab30-NH2, as MR-502 (D-Ala2, 5F-Phe 6, Ser28, Arg29,Gab30-NH 2-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.

Original languageEnglish
Pages (from-to)104-112
Number of pages9
JournalPeptides
Volume52
DOIs
StatePublished - Feb 1 2014

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Keywords

  • Cardioprotection
  • hGHRH agonist
  • hGHRH(1-29)
  • s.c. administration

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Physiology
  • Cellular and Molecular Neuroscience

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