Hidetoshi Asai, Kiyoshi Kinoshita, Michio Yamamura and Yuzo Matsuoka
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-2-5O Kawagishi,
Toda, Saitama 335-8505, Japan
Abstract: In order to analyze the receptor properties of central
nervous system (CNS)-stimulant thyrotropin-releasing hormone (L-pyroglutamyl-L-histidyl-L-prolinamide,
TRH), we evaluated the binding of TRH and its analog taltirelin hydrate
((-)-N-[(S)
-hexahydro-1-methyl-2,6-dioxo-4-pyrimidinylcarbonyl]-L-histidyl-L-prolinamide tetrahydrate; taltirelin, TA-0910) in rat anterior pituitary and several brain regions. There was a specific binding of [3H]methyl TRH (MeTRH) in the anterior pituitary, hypothalamus, brain stem, cerebral cortex and cerebellum with Kd values of 1.0 - 1.6 nM. The inhibition of [3H]MeTRH binding by TRH and taltirelin was monophasic in the anterior pituitary, hypothalamus and brain stem with Ki values of 6.3 - 8.0 nM and 145.5 - 170.4 nM for TRH and taltirelin, respectively. In contrast, the biphasic inhibition was revealed in the cerebral cortex and cerebellum. The Ki values for TRH and taltirelin were 4.1 - 4.3 nM and 67.8 - 73.4 nM for the high affinity binding site and 3.6 - 4.2 microM and 82.3 - 197.5 microM for the low affinity binding site, respectively. Addition of 100 microM GTP or its analog 5'-guanylylimidodiphosphate (Gpp[NH]p) affected neither the biphasic inhibition by TRH nor that by taltirelin. Thus the results suggest the presence of distinct high and low affinity TRH receptors in the CNS in contrast to the pituitary.
Keywords: TRH (thyrotropin-releasing hormone), Taltirelin (TA-0910, TRH
analog), Receptor binding, Pituitary, Brain region