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Structure‐activity studies of hydrophobic amino acid replacements at positions 9, 11 and 16 of glucagon

1997; Wiley; Volume: 49; Issue: 4 Linguagem: Inglês

10.1111/j.1399-3011.1997.tb01129.x

1399-3011

Noel S. Sturm, Ann Marie Hutzler, CLINTON S. DAVID, Bassem Y. Azizeh, Dev Trivedi, Victor J. Hruby,

Chemical Synthesis and Analysis

We have designed and synthesized eight compounds 2‐9 which incorporate neutral, hydrophobic amino acid residues in positions 9, 11 and 16 of the glucagon molecule: (2) [desHis 1 ,Va1 9 ,11e 11,16 ] glucagon amide, (3) [desHis 1 ,Val 9,11,16 ]glucagon amide, (4) [desHis 1 ,Va1 9 ,Leu 11,16 ]glucagon amide, (5) [desHis 1 ,Nle 9 ,11e 11,16 ]glucagon amide, (6) [desHis 1 ,Nle 9 ,Val 11,16 ]glucagon amide, (7) [desHis 1 ,Nle 9 ,Leu 11,16 ]glucagon amide, (8) [desHis 1 ,Val 9 ,Leu 11,16 ,Lys 17,18 ,Glu 21 ]glucagon amide and (9) [desHis 1 ,Nle 9 ,Leu 11,16 ,Lys 17,18 ,Glu 21 ]glucagon amide. The effect of neutral, hydrophobic residues at positions 9, 11 and 16 led to good binding to the glucagon receptor. Compared to glucagon (IC 50 = 1.5 nM), analogues 2‐9 were found to have IC 50 values of 6.0, 6.0, 11.0, 9.0, 2.5, 2.8, 6.5 and 7.0 nM, respectively. When these compounds were tested for their ability to block adenylate cyclase (AC) activity, they were found to be antagonists having no stimulation of adenyl cyclase, with P A 2 , values of 6.15, 6.20, 6.30, 7.25, 6.10, 7.30, 6.25 and 7.25, respectively. © Munksgaard 1997.