SYNTHESIS AND BIOLOGICAL EVALUATION OF SUPERACTIVE AGONISTS OF GROWTHHORMONE-RELEASING HORMONE

Analogs of the 29 amino acid sequence of human growth hormone-releasin g hormone (hGH-RH) with agmatine (Agm) in position 29, desaminotyrosin e (Dat) in position 1, norleucine (Nle) in position 27, and L-alpha-am inobutyric acid (Abu) in position 15 have been synthesized, and their biological activity was evaluated. Some peptides contained one or two residues of ornithine (Orn) instead of Lys in positions 12 and 21 and additional replacements in positions 8 and 28. All analogs were found to be more potent than hGH-RH-(1-29)-NH2 in the superfused rat pituita ry cell system. In tests in vivo in rats after subcutaneous administra tion, the analogs JI-22, ,Orn(12,21),Abu(15),Nle(27),Agm(29)]hGH-RH-(1 -29); JI-34, Dat(1),Orn(12,21),Abu(15),Nle(27),Asp(28),Agm(29)] hGH-RH -(1-29); JI-36, [Dat(1),Thr(8),Orn(12,21), Abu(15),Nle(27),Asp(28),Agm (29)]hGH-RH-(1-29); and JI-38, Gln(8),Orn(12,21),Abu(15),Nle(27),Asp(2 8),Agm(29)] hGH-RH-(1-29) displayed a potency 44.6, 80.9, 95.8, and 71 .4 times greater, respectively, than that of hGH-RH-(1-29)-NH2 at 15 m in and 217.1, 89.7, 87.9, and 116.8 times greater at 30 min. After int ravenous administration, JI-22, JI-36, and JI-38 were 3.2-3.8 times mo re potent than hGH-RH-(1-29)-NH2 at 5 min and 6.1-8.5 times more activ e at 15 min. All analogs were found to have higher binding affinities for GH-RH receptors on rat pituitary cells than hGH-RH-(1-29)-NH2. Bec ause of high activity and greater stability, these analogs could be co nsidered for therapy of patients with growth hormone deficiency.