The interaction of benzodiazepines with thyrotropin-releasing hormone receptors on clonal pituitary cells.
1. Seven benzodiazepines were investigated for their ability to interact with receptors for thyrotropin-releasing hormone (TRH) on GH3 and GH4C1 pituitary tumour cells. 2. Midazolam and chlordiazepoxide were the most potent inhibitors of TRH-induced [3H]-inositol phosphate formation with Ki values in the low micromolar range. The antagonism was competitive in nature and was increased in potency at sub-physiological temperatures. 3. None of the agents examined antagonized bombesin-induced [3H]-inositol phosphate formation in GH4C1 cells. 4. While the ability of benzodiazepines to interact with the GABA receptor-chloride channel ionophore is markedly stereospecific, little difference was evident in the ability of (+)- and (-)-4-methylmidazolam (Ro 21-5656 and Ro 21-5657) to compete with TRH at its receptor. 5. Recently it has been suggested that, in contrast to phosphatidylinositol hydrolysis, the TRH-induced breakdown of phosphatidylinositol polyphosphates is transient in clonal pituitary cells. Addition of chlordiazepoxide to TRH-stimulated GH3 cells up to 60 min after initiating the reaction leads, however, to an immediate decline in the cellular content of inositol trisphosphate. This indicates that TRH-induced phosphatidylinositol 4,5-bisphosphate hydrolysis is not transient.
Joels
L A
LA
Department of Pharmacology, School of Pharmacy, London.
Drummond
A H
AH
D001569:Benzodiazepines / Q000494:pharmacology*; D002460:Cell Line; D002999:Clone Cells; D007295:Inositol Phosphates / Q000096:biosynthesis*; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter / Q000187:drug effects* / Q000378:metabolism; D018025:Receptors, Thyrotropin-Releasing Hormone; D013329:Structure-Activity Relationship; D013403:Sugar Phosphates / Q000096:biosynthesis*; D013973:Thyrotropin-Releasing Hormone / Q000037:antagonists & inhibitors*
D007295:Inositol Phosphates; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter; D018025:Receptors, Thyrotropin-Releasing Hormone; D013403:Sugar Phosphates; D001569:Benzodiazepines; D013973:Thyrotropin-Releasing Hormone