title: Synthesis of new potent agonistic analogs of growth hormone-releasing hormone (GHRH) and evaluation of their endocrine and cardiac activities.
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-Tyr(1)-JI-38), MR-361(N-Me-Tyr(1), D-Ala(2)-JI-38) and MR-367(N-Me-Tyr(1), D-Ala(2), Asn(8)-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 Arg(29)-NHCH3 as in MR-403 (N-Me-Tyr(1), D-Ala(2), Arg(29)-NHCH3-JI-38), MR-406 (N-Me-Tyr(1), Arg(29)-NHCH3-JI-38) and MR-409 (N-Me-Tyr(1), D-Ala(2), Asn(8), Arg(29)-NHCH3-JI-38), and MR-410 (N-Me-Tyr(1), D-Ala(2), Thr(8), Arg(29)-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-Tyr(1), D-Ala(2), Arg(29), Apa(30)-NH2-JI-38), and with Gab(30)-NH2, as MR-502 (D-Ala(2), 5F-Phe(6), Ser(28), Arg(29),Gab(30)-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.
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL, United States.
authors.forename: Renzhi
authors.initials: R
authors.lastname: Cai
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL, United States; Division of Hematology/Oncology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, United States; Division of Endocrinology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, United States. Electronic address: andrew.schally@va.gov.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL, United States.
authors.forename: Tengjiao
authors.initials: T
authors.lastname: Cui
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States.
authors.forename: Luca
authors.initials: L
authors.lastname: Szalontay
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL, United States.
authors.forename: Gabor
authors.initials: G
authors.lastname: Halmos
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Interdisciplinary Stem Cell Institute, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Sha
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL, United States.
authors.forename: Magdolna
authors.initials: M
authors.lastname: Kovacs
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States.
authors.forename: Miklos
authors.initials: M
authors.lastname: Jaszberenyi
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States.
authors.forename: Jinlin
authors.initials: J
authors.lastname: He
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Department of Urology, Florida International University, Herbert Wertheim College of Medicine, Miami, FL, United States.
authors.forename: Ferenc G
authors.initials: FG
authors.lastname: Rick
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; Division of Cardiology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, United States.
authors.forename: Petra
authors.initials: P
authors.lastname: Popovics
authors.affiliation: Interdisciplinary Stem Cell Institute, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, United States.
authors.forename: Rosemeire
authors.initials: R
authors.lastname: Kanashiro-Takeuchi
authors.affiliation: Division of Cardiology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, United States; Interdisciplinary Stem Cell Institute, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, United States.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL, United States; Division of Hematology/Oncology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, United States.
authors.forename: Norman L
authors.initials: NL
authors.lastname: Block
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, United States; South Florida VA Foundation for Research and Education, Miami, FL, United States; Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL, United States.
authors.forename: Marta
authors.initials: M
authors.lastname: Zarandi
mesh_terms: D000376:Agmatine; D000818:Animals; D004703:Endocrine System / Q000378:metabolism*; D013007:Growth Hormone-Releasing Hormone / Q000819:agonists* / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D010455:Peptides; D000376:Agmatine; D013007:Growth Hormone-Releasing Hormone
keywords: Cardioprotection; hGHRH agonist; hGHRH(1–29); s.c. administration