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Synthesis and in vitro and in vivo activity of analogs of growth hormone‐releasing hormone (GH‐RH) with C ‐terminal agmatine

1990; Wiley; Volume: 36; Issue: 6 Linguagem: Inglês

10.1111/j.1399-3011.1990.tb00988.x

0367-8377

Márta Zarándi, Valér Csernus, L. Bokser, S. Bajusz, Kate Groot, Andrew V. Schally,

Neuropeptides and Animal Physiology

In the search for more active analogs of human growth hormone‐releasing hormone (GH‐RH), 37 new compounds were synthesized by solid phase methodology, purified, and tested biologically. Most of the analogs contained a sequence of 27 amino acids and N ‐terminal desaminotyrosine (Dat) and C ‐terminal agmatine (Agm), which are not amino acids. In addition to Dat in position 1 and Agm in position 29, the majority of the analogs had Ala 15 and Nle 27 substitutions and one or more additional L‐ or D‐amino acid modifications. [Dat 1 , Ala 15 , Nle 27 ]GH‐RH(1‐28)Agm (MZ‐2‐51) was the most active analog. Its in vitro GH‐releasing potency was 10.5 times higher than that of GH‐RH(1‐29)NH 2 and in the i.v. in vivo assay, MZ‐2‐51 was 4‐5 times more active than the standard. After s.c. administration to rats, MZ‐2‐51 showed an activity 34 times higher at 15min and 179 times greater at 30min than GH‐RH(1‐29)NH 2 and also displayed a prolonged activity. D‐Tyr 10 , D‐Lys 12 , and D‐Lys 12 homologs of MZ‐2‐51 also showed enhanced activities. Thus, [Dat 1 , D‐Tyr 10 , Ala 15 , Nle 27 ]GH‐RH(1‐28)Agm (MZ‐2‐159), [Dat 1 , D‐Lys 12 , Ala 15 , Nle 27 ]GH‐RH(1‐28)AGM (MZ‐2‐57), and [Dat 1 , Ala 15 , D‐Lys 21 , Nle 27 ]GH‐RH(1‐28)Agm (MZ‐2‐75) were 4‐6 times more active in vitro than GH‐RH(1‐29)NH 2 . In vivo , after i.v. administration, analog MZ‐2‐75 was equipotent and analogs MZ‐2‐159 and MZ‐2‐57 about twice as potent as the standard. After S.C. administration, the potencies of MZ‐2‐57 and MZ‐2‐75 were 10‐14 times higher than the standard at 15 min and 45‐89 times greater when determined at 30 min. Most of the analogs containing two or more D‐amino acid substitutions were less active than GH‐RH(1‐29)NH 2 or inactive. Our studies indicate that very potent GH‐RH analogs can result from the combination of agmatine in position 29 with other substitutions.