TY - JOUR
T1 - Synthesis of new potent agonistic analogs of growth hormone-releasing hormone (GHRH) and evaluation of their endocrine and cardiac activities
AU - Cai, Renzhi
AU - Schally, Andrew V.
AU - Cui, Tengjiao
AU - Szalontay, Luca
AU - Halmos, Gabor
AU - Sha, Wei
AU - Kovacs, Magdolna
AU - Jaszberenyi, Miklos
AU - He, Jinlin
AU - Rick, Ferenc G.
AU - Popovics, Petra
AU - Kanashiro-Takeuchi, Rosemeire
AU - Hare, Joshua M.
AU - Block, Norman L.
AU - Zarandi, Marta
N1 - Funding Information:
These studies were supported by the Medical Research Service of the Veterans Affairs Department , Departments of Pathology and Medicine, Division of Hematology/Oncology of the Miller School of Medicine University of Miami , South Florida Veterans Affairs Foundation for Research and Education (all to AVS), NIH RO1 HL-107110 (to JMH) and the L. Austin Weeks Endowment for Urologic Research (NLB) and grants from the Wallace H. Coulter Foundation SB26MT66142E (to AVS) for the development of GHRH agonists for translation research. This work of GH was also supported by TAMOP 4.2.2.A-11/1/KONV-2012-0025 project (GH). This project is co-financed by the European Union and the European Social Fund . Petra Popovics was supported by a stipend program of the Department of Medicine, Dresden and by the Helmholtz Alliance ICEMED (Imaging and Curing Environmental Metabolic Diseases) through the Initiative and Networking Fund of the Helmholtz Association .
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
KW - Cardioprotection
KW - hGHRH agonist
KW - hGHRH(1-29)
KW - s.c. administration
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U2 - 10.1016/j.peptides.2013.12.010
DO - 10.1016/j.peptides.2013.12.010
M3 - Article
C2 - 24373935
AN - SCOPUS:84892692521
VL - 52
SP - 104
EP - 112
JO - Peptides
JF - Peptides
SN - 0196-9781
ER -