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 -NHCH 3 as in MR-403 (N-Me-Tyr 1 , D-Ala 2 , Arg 29 -NHCH 3 -JI-38), MR-406 (N-Me-Tyr 1 , Arg 29 -NHCH 3 -JI-38) and MR-409 (N-Me-Tyr 1 , D-Ala 2 , Asn 8 , Arg 29 -NHCH 3 -JI-38), and MR-410 (N-Me-Tyr 1 , D-Ala 2 , Thr 8 , Arg 29 -NHCH 3 -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 -NH 2 such as MR-326 (N-Me-Tyr 1 , D-Ala 2 , Arg 29 , Apa 30 -NH 2 -JI-38), and with Gab 30 -NH 2 , as MR-502 (D-Ala 2 , 5F-Phe 6 , Ser 28 , Arg 29 ,Gab 30 -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.