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

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.