Synthesis and in vitro bioactivity of human growth hormone-releasing factor analogs substituted at position-1

Eight position-1 analogs of the 40-amino acid fragment and two position-1 analogs of human growth hormone-releasing factor were synthesized by solid phase methodology and their capacity to release growth hormone was determined using rat anterior pituitary cells in monolayer culture. Relative to hGRF(1-40)OH, which was arbitrarily assigned a potency value of 1, [D-Tyr1]hGRF(1-40)OH, [Phe1]hGRF(1-40)OH, [Trp1]hGRF(1-40)OH, [His1]hGRF(1-40)OH, [Ala1]hGRF(1-40)OH, [(-Ac)Tyr1]hGRF(1-40)OH, Arg0-hGRF(1-40)OH and Ala0-hGRF(1-40)OH have potencies of 0.022, 0.038, 0.003, 0.351, 0.010, 0.032, 0.002 and 0.007 respectively. Relative to hGRF(1-44)NH2 = 1, [(3-Me)His1]hGRF(1-44)NH2 and [(O-Me)Tyr1]hGRF(1-44)NH2 have potencies of 0.132 and 0.001 respectively. These results demonstrate the prerequisite for an aromatic residue at position-1 for potent biological activity and also suggest that the capacity for hydrogen bond formation with the first residue is required for full receptor-ligand interaction.