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

被引:62
作者
Cai, Renzhi [1 ,2 ,3 ]
Schally, Andrew V. [1 ,2 ,3 ,4 ,5 ]
Cui, Tengjiao [1 ,2 ,3 ]
Szalontay, Luca [1 ,2 ]
Halmos, Gabor [1 ,2 ,3 ]
Sha, Wei [1 ,2 ,7 ]
Kovacs, Magdolna [1 ,2 ,3 ]
Jaszberenyi, Miklos [1 ,2 ]
He, Jinlin [1 ]
Rick, Ferenc G. [1 ,2 ,8 ]
Popovics, Petra [1 ,6 ]
Kanashiro-Takeuchi, Rosemeire [7 ]
Hare, Joshua M. [6 ,7 ]
Block, Norman L. [1 ,2 ,3 ,4 ]
Zarandi, Marta [1 ,2 ,3 ]
机构
[1] Vet Affairs Med Ctr, Inst Endocrine Polypeptide & Canc, Miami, FL 33125 USA
[2] South Florida VA Fdn Res & Educ, Miami, FL USA
[3] Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL 33136 USA
[4] Univ Miami, Miller Sch Med, Dept Med, Div Hematol Oncol, Miami, FL 33136 USA
[5] Univ Miami, Miller Sch Med, Dept Med, Div Endocrinol, Miami, FL 33136 USA
[6] Univ Miami, Miller Sch Med, Dept Med, Div Cardiol, Miami, FL 33136 USA
[7] Univ Miami, Miller Sch Med, Dept Med, Interdisciplinary Stem Cell Inst, Miami, FL 33136 USA
[8] Florida Int Univ, Herbert Wertheim Coll Med, Dept Urol, Miami, FL 33199 USA
关键词
hGHRH agonist; hGHRH(1-29); s.c; administration; Cardioprotection; GRF ANALOGS; PANCREATIC-ISLETS; ENZYMATIC DEGRADATION; MYOCARDIAL-INFARCTION; BIOLOGICAL EVALUATION; SEQUENCE-ANALYSIS; INVITRO; BINDING; HYPOTHALAMUS; BIOACTIVITY;
D O I
10.1016/j.peptides.2013.12.010
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
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 beensynthesized and evaluated biologically in an endeavor to produce more potent compounds. "Agmatineanalogs", 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 GHrelease upon subcutaneous administration in vivo and binding in vitro. Modification with N-Me-Tyr1andArg29NHCH3as in MR-403 (N-Me-Tyr1, D-Ala2, Arg29-NHCH3-JI-38), MR-406 (N-Me-Tyr1, Arg29-NHCH3JI- 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 mostpotent GHRH agonistic analogs so far developed. Analogs with Apa30-NH2such 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, Gab30NH2- JI-38) also exhibited much higher potency than JI-38 upon i. v. administration. The relationshipbetween the GH-releasing potency and the analog structure is discussed. Fourteen GHRH agonists withthe highest endocrine potencies were subjected to cardiologic tests. MR-409 and MR-356 exhibited higherpotency than JI-38 in activating myocardial repair in rats with induced myocardial infarction. As theprevious class of analogs, exemplified by JI-38, had shown promising results in multiple fields includingcardiology, diabetes and wound healing, our new, more potent, GHRH agonists should manifest additionalefficacy for possible medical applications. Published by Elsevier Inc.
引用
收藏
页码:104 / 112
页数:9
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