A novel TRH analog, YM14673, stimulates intracellular signaling systems in the brain more potently than predicted by its pituitary actions.
YM14673, a novel analog of TRH, substituting the (oxo-azetidinyl)carbonyl moiety for the pyroglutamyl moiety of TRH, was synthesized and its brain action was evaluated using rat brain slices in vitro. The addition of YM14673 engendered significant and dose-dependent increases in cyclic AMP formation in the hypothalamus and inositol phosphates (IP) accumulation in the cerebellum. The actions of YM14673 did not statistically differ from those of TRH on brain tissues. However, YM14673 did not show a direct interference with TRH binding in the brain membranes. [3H]YM14673 underwent to the same extent the enzymatic degradation by type II pyroglutamyl aminopeptidase as did TRH. As compared with TRH, YM14673 had a lower activity with respect to stimulation of thyrotropin secretion and accumulation of IP in the anterior pituitaries. The data imply that YM14673 possessed potent stimulatory actions on brain intracellular signaling systems with weak hypophyseal activities. These actions of YM14673 were not due to a direct interference with brain TRH binding or a nature impervious to a TRH-degrading enzyme. The present study indicates that the larger doses of YM14673 than TRH can be used for medical treatment of neurological and neuromuscular disorders without strong influences on pituitary functions.
First Department of Internal Medicine, Gunma University, School of Medicine, Maebashi, Japan.
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M
Mori
T
T
Iriuchijima
M
M
Yamada
M
M
Murakami
S
S
Kobayashi
D000818:Animals; D001384:Azetidines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D000242:Cyclic AMP / Q000096:biosynthesis; D004151:Dipeptides / Q000494:pharmacology*; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000502:physiology; D011751:Pyroglutamyl-Peptidase I / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013972:Thyrotropin / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
D001384:Azetidines; D004151:Dipeptides; D007295:Inositol Phosphates; D013973:Thyrotropin-Releasing Hormone; C054995:azetirelin; D013972:Thyrotropin; D000242:Cyclic AMP; D011751:Pyroglutamyl-Peptidase I