Characterization of the binding of [3H](+)-pentazocine to sigma recognition sites in guinea pig brain.
The selective sigma compound (+)-pentazocine was radiolabeled and its binding characteristics in guinea pig brain membranes were investigated. [3H](+)-Pentazocine bound to a single high-affinity site with a KD of 2.9 nM and a Bmax of 1998 fmol/mg protein. Saturation was achieved at a ligand concentration of 15 nM. Maximal specific binding was observed at 37 degrees C and was greater than 90% of total binding. Equilibrium was reached by 120 min and dissociation was complete by 420 min, with a t1/2 of 121 min. Li+, Ca2+ and Mg2+ inhibited binding at high concentrations, and binding was insensitive to adenyl and guanyl nucleotides. Stereoselectivity was observed for the inhibition of binding by benzomorphans, 3-(3-hydroxyphenyl)-N-propylpiperidine and butaclamol, and the (+) enantiomers and alpha diastereomers of pentazocine and cyclazocine were more potent than their corresponding (-) enantiomers and beta diastereomers. The rank order of potency for the sigma reference agents to displace [3H](+)-pentazocine binding was similar to that reported using the [3H]sigma ligands dextromethorphan, 1,3-di(2-tolyl)guanidine and (+)-3-(3-hydroxyphenyl)-N-propylpiperidine. Haloperidol, (+)-pentazocine, (+)-3-(3-hydroxyphenyl)-N-propylpiperidine and rimcazole were competitive inhibitors of binding to the [3H](+)-pentazocine-defined sigma recognition site, suggesting that these different structural classes of compounds all bind to a single molecular entity.
Department of Enzymology and Receptor Biochemistry, Sterling Winthrop Pharmaceuticals Research Division, Malvern, PA 19355-1314.
D L
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DeHaven-Hudkins
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Fleissner
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Ford-Rice
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D006168:Guinea Pigs; D006220:Haloperidol / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D010423:Pentazocine / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D017480:Receptors, sigma / Q000187:drug effects / Q000378:metabolism
D014150:Antipsychotic Agents; D002227:Carbazoles; D015259:Dopamine Agents; D010880:Piperidines; D017480:Receptors, sigma; C026539:preclamol; C034931:rimcazole; D006220:Haloperidol; D010423:Pentazocine