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

Publication date: February 2014 Source:Peptides, Volume 52

Author(s): 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 Kanashiro-Takeuchi , Joshua M. Hare , Norman L. Block , Marta Zarandi

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.