Mechanisms of brain inactivation of centrally-acting thyrotrophin-releasing hormone (TRH) analogues: a high-performance liquid chromatography study.

High-performance liquid chromatography (HPLC) was used to investigate the degradation in vitro of several centrally-acting analogues of thyrotrophin-releasing hormone (TRH) by two subcellular fractions prepared from different areas of rat brain. Of the seven analogues studied, RX77368 (pGlu-His-(3,3'-dimethyl)-ProNH2) was the most stable analogue, showing only a small amount of degradation by the particulate fraction containing a pyroglutamyl aminopeptidase, whereas the other analogues (RX74355, CG3509, CG3703, [3MeHis]TRH, PGHPA and MK771) showed varying degrees of resistance to degradation by this enzyme and the proline endopeptidase in the soluble fraction. However, TRH was rapidly inactivated to its deamidated form, TRH-OH and the histidyl-proline diketopiperazine by both fractions. The relative stability of these TRH analogues to enzyme action may provide some explanation for their enhanced biological activity in vivo.