title: Inhibition of [3H][3-MeHis2]thyrotropin releasing hormone recognition sites in the rat brain by tifluadom, a kappa opiate receptor agonist.
abstract: The effect of tifluadom (TIF), a postulated kappa-opiate agonist with a benzodiazepine (Bz) structure, on the binding of [3H][3-MeHis2]thyrotropin releasing hormone [( 3H]MeTRH) to receptors for thyrotropin releasing hormone (TRH) in membranes from rat brain was determined. Tifluadom inhibited the binding of [3H]MeTRH with an IC50 value of 1.88 microM. When the binding was carried out in the presence of an IC20 concentration of tifluadom, the Bmax value of [3H]MeTRH was decreased by 20% but no change in the Kd value was noted, indicating that the inhibition was apparently noncompetitive. Ro 15-1788 a benzodiazepine antagonist, as well as bicuculline, a gamma-aminobutyric acid (GABA) antagonist did not antagonize the effect of tifluadom on the binding of [3H]MeTRH suggesting that the benzodiazepine receptors are not involved in the action of tifluadom. Since tifluadom is suggested to be a kappa-opioid agonist, the effect of other kappa-opiate ligands were also tested for their ability to affect TRH receptors. The drugs used were ethylketocyclazocine, dynorphin(1-13) and 5-bromo-6-(2-imidazoline-2-ylamino)quinoxaline (U-50,488H). The order of potency of these compounds to inhibit the binding of [3H]MeTRH to membrane from the rat brain was in the following order: tifluadom greater than U-50,488H greater than dynorphin-(1-13) greater than ethylketocyclazocine. It is concluded that tifluadom inhibits the binding of [3H]MeTRH to receptors in brain in a noncompetitive manner. The effect does not appear to be mediated through benzodiazepine receptors but possibly through kappa-opiate receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000704:Analysis of Variance; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D003496:Cyclazocine / Q000031:analogs & derivatives / Q000378:metabolism; D004399:Dynorphins / Q000378:metabolism; D016314:Ethylketocyclazocine; D007700:Kinetics; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism; D011759:Pyrrolidines / Q000378:metabolism; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D011957:Receptors, Opioid / Q000378:metabolism*; D017473:Receptors, Opioid, kappa; D018025:Receptors, Thyrotropin-Releasing Hormone; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D010446:Peptide Fragments; D011759:Pyrrolidines; D017981:Receptors, Neurotransmitter; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D018025:Receptors, Thyrotropin-Releasing Hormone; D001569:Benzodiazepines; C014109:thyrotropin-releasing hormone, 3-Me-; D016314:Ethylketocyclazocine; D013973:Thyrotropin-Releasing Hormone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C026843:dynorphin (1-13); D004399:Dynorphins; D003496:Cyclazocine; D011761:Pyrrolidonecarboxylic Acid; C035470:tifluadom