Synthetic TRF (thyrotropin releasing factor) analogues. II. pGlu-N3imMe-His-Pro-NH2: a synthetic analogue with specific activity greater than that of TRF2.

Abstract

A series of synthetic analogues of TRF (thyrotropin releasing factor, pGlu-His-Pro-NH2) have been tested for biological activity. As part of this series, two dipeptide and two tripeptide derivatives were prepared which had a single methyl group on one nitrogen of the imidazole ring. In vivo, pGlu-N1imMe-His-Pro-NHo exhibited only 20 U/mg specific activity (TRF = 50,000 U/mg) or 1/2500 of the activity of TRF, but pGlu-N3imMe-His-Pro-NH2 showed approximately 400,000 U/mg or 8 times greater activity than TRF. The pGlu-N3imMe-His-Pro-NH2 is also more active than TRF in vitro. The dipeptides pGlu-His-OMe and pGlu-N1imMe-His-OMe had no detectable biological activity (< 0.25 U/mg and < 1.25 U/mg respectively). However, pGlu-N3imMe-His-OMe had slight biological activity (10 U/mg). Therefore, addition of a methyl to the N3im of histidine enhances the TSH releasing activity of both TRF and pGlu-His-OMe. The response to pGlu-N3imMe-His-Pro-NH2 is decreased by pretreatment of the animals with triiodothyronine as is the case for TRF. Furthermore, the biological activity of pGlu-N3imMe-His-Pro-NH2 like that of TRF is destroyed by incubation in plasma. Of all the TRF analogues tested so far by us or reported by others, pGlu-N3im His-Pro-NH2 qualitatively similar to TRF in its biological action is the only compound to show higher specific activity than that of the native molecule. (Endocrinology89: 1485, 197)