title: Synthesis and central nervous system actions of thyrotropin-releasing hormone analogues containing a dihydroorotic acid moiety.
abstract: 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.
authors.affiliation: Research Laboratory of Applied Biochemistry, Tanabe Seiyaku Company, Ltd., Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.forename: H
authors.initials: H
authors.lastname: Sugano
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.forename: M
authors.initials: M
authors.lastname: Yamamura
authors.forename: R
authors.initials: R
authors.lastname: Ishida
mesh_terms: D000758:Anesthesia; D002490:Central Nervous System / Q000187:drug effects*; D055598:Chemical Phenomena; D002621:Chemistry; D007035:Hypothermia / Q000139:chemically induced; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D009963:Orotic Acid / Q000031:analogs & derivatives*; D010424:Pentobarbital / Q000037:antagonists & inhibitors; D012110:Reserpine / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013972:Thyrotropin / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: C065049:TA 0910; C004768:4,5-dihydroorotic acid; D013973:Thyrotropin-Releasing Hormone; D009963:Orotic Acid; D012110:Reserpine; D013972:Thyrotropin; D010424:Pentobarbital