title: Stereoselectivity of kappa-opiate receptor ligands in inhibiting the binding of [3H][3-MeHis2]thyrotrophin releasing hormone to brain membranes.
abstract: The effect of (+/-)-, (-)- and (+)-isomers of several ligands for kappa-opiate receptors on the binding of [3H][3-MeHis2]-thyrotrophin releasing hormone ([3H]MeTRH) to rat brain membranes has been determined. [3H]MeTRH bound to rat brain membranes at a single high affinity site with maximal binding capacity (Bmax) of 48 +/- 2 fmol(mg protein)-1, and an apparent dissociation constant, Kd of 4.6 +/- 0.2 nM. At a concentration of 2 nM, the specific binding of [3H]MeTRH was 12.3 +/- 0.6 fmol(mg protein)-1. The isomers of ketocyclazocine, tifluadom (1-methyl-2-(3-thienylcarbonyl) aminomethyl-5-(2-fluorophenyl) H-2,3-dihydro-1,4-benzodiazepine), and alpha-5,9-diethyl-2'-hydroxy-2-(3-furylmethyl)-6,7-benzomorphan [MR 2266 (-), MR 2267 (+)] were used for interaction studies. The (-)-isomer of each of the above drugs was more potent than the (+)-form in inhibiting the binding of [3H]MeTRH to brain membranes, whereas the (+/-)-forms had activity intermediate between (-)- and (+)-forms. The order of activity of kappa-ligands was tifluadom greater than MR 2266 greater than ketocyclazocine. It is concluded that kappa-opiate drugs inhibit the binding of [3H]MeTRH to brain membranes in a stereoselective manner with tifluadom being the most potent drug.
mesh_terms: D000818:Animals; D001575:Benzomorphans / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism*; D017473:Receptors, Opioid, kappa; D013237:Stereoisomerism; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D001575:Benzomorphans; D009292:Narcotic Antagonists; D009294:Narcotics; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; C014109:thyrotropin-releasing hormone, 3-Me-; C027247:MR 2266; D013973:Thyrotropin-Releasing Hormone; D011761:Pyrrolidonecarboxylic Acid