SYNTHESIS AND CENTRAL-NERVOUS-SYSTEM ACTIONS OF THYROTROPIN-RELEASING-HORMONE ANALOGS CONTAINING A DIHYDROOROTIC ACID MOIETY

A series of thyrotropin-releasing hormone (TRH) analogues in which the pyroglutamic acid residue was replaced by (S)-4,5-dihydroorotic acid (Dio-OH) and the related derivatives were prepared. Their central nervous system actions based on spontaneous locomotor activity, antagonistic effect on reserpine-induced hypothermia, and antagonistic effect on pentobarbital anesthesia were evaluated and the structure-activity relationships are discussed. Of these, (1-methyl-(S)-4,5-dihydroorotyl)-L-histidyl-L-prolinamide (14b) showed the most potent activities, which were 30–90 times greater than those of TRH. Moreover, the thyrotropin-releasing activity of 14b was about 50 times weaker than that of TRH, and compound 14b (TA-0910) was selected as a potent candidate. © 1990, American Chemical Society. All rights reserved.