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Potent agonists of growth hormone‐releasing hormone

1992; Wiley; Volume: 39; Issue: 3 Linguagem: Inglês

10.1111/j.1399-3011.1992.tb00791.x

0367-8377

Márta Zarándi, Péter Serfózó, JOZSEF ZSIGO, L. Bokser, Tamás Janáky, Donald B. Olsen, S. Bajusz, Andrew V. Schally,

Chemical Synthesis and Analysis

Analogs of the 29 amino acid sequence of growth hormone‐releasing hormone (GH‐RH) with agmatine (Agm) in position 29 have been synthesized by the solid phase method, purified, and tested in vitro and in vivo. The majority of the analogs contained desaminotyrosine (Dat) in position 1, but a few of them had Tyr 1 , or N‐MeTyr 1 . Some peptides contained one or more additional l ‐ or d ‐amino acid substitutions in positions 2, 12, 15, 21, 27, and/or 28. Compared to the natural sequence of GH‐RH(1‐29)NH 2 , [Dat′,Ala 15 ]GH‐RH(1‐28)Agm (MZ‐3‐191) and [ d ‐Ala 2 ,Ala 15 ]GH‐RH(l‐28)Agm (MZ‐3‐201) were 8.2 and 7.1 times more potent in vitro, respectively. These two peptides contained Met 27 . Their Nle 27 analogs, [Dat I ,Ala 15 ,Nle 27 ]GH‐RH(1‐28)Agm(MZ‐2‐51), prepared previously (9), and [ D ‐Ala 2 ,Ala 15 ,Nle 28 ]GH‐RH(l‐28)Agm(MZ‐3‐195) showed relative in vitro potencies of 10.5 and 2.4, respectively. These data indicate that replacement of Met 27 by Nle 27 enhanced the GH‐releasing activity of the analog when the molecule contained Dat 1 ‐Ala 2 residues at the N ‐terminus, but peptides containing Tyr 1 ‐D‐Ala 2 in addition to Nle 27 showed decreased potencies. Replacement of Ser 28 with Asp in multi‐substituted analogs of GH‐RH(l‐28)Agm resulted in a decrease in in vitro potencies compared to the parent compound. Thus, the Ser 28 ‐containing MZ‐2‐51, and [Dat 1 ,Ala 15 , d ‐Lys 21 ,Nle 27 ]GH‐RH(l‐28)Agm, its Asp 28 homolog (MZ‐3‐149), possessed relative activities of 10.5 and 5.6, respectively. In vivo after the iv injection, the analogs [Dat 1 ,Ala 15 ,Nle 27 ,Asp 28 ]GH‐RH(l‐28)Agm (MZ‐3‐149), [Dat 1 , Ala 15 ]GH‐RH(l‐28)Agm, (MZ‐3‐191) and [ d ‐Ala 2 ,Ala ,5 ]GH‐RH(l‐28)Agm (MZ‐3‐201) showed a potency equivalent to 7.6, 4.9 and 3.3 times that of GH‐RH(1‐29)NH 2 , respectively, at 5 min and 20.3, 4.3 and 1.7 times higher, respectively, at 15 min. After sc administration, analogs MZ‐3‐149, MZ‐3‐191, and MZ‐3‐201 were shown to be 63.7, 55.2 and 56.8 times more potent than the parent hormone at 15 min and 57.6, 60.6, and 42.6 times more active, respectively, at 30 min. In addition, MZ‐3‐149 had prolonged GH‐releasing activity as compared to the standard, and proved to be more potent than MZ‐2‐51, the most active member of our previous series (8, 9). Our studies indicate that very potent GH‐RH analogs can result from the combination of agmatine in position 29 with other substitutions.