[3H]DuP 734 [1-(cyclopropylmethyl)-4-(2'-(4''-fluorophenyl)-2'- oxoethyl)-piperidine HBr]: a receptor binding profile of a high-affinity novel sigma receptor ligand in guinea pig brain.
The in vitro binding properties of 1-(cyclopropylmethyl)-4-(2'-(4''-fluorophenyl)-2'-oxoethyl)pipe ridi ne HBr, [3H]DuP 734, a novel sigma receptor ligand, were examined in homogenates of guinea pig brain. Specific [3H]DuP 734 binding (10 microM haloperidol-displaceable) in cerebellum was dependent on pH, temperature and membrane protein concentration, reversible, saturable and of high affinity (KD = 228 +/- 34 pM; Bmax = 3856 +/- 340 fmol/mg protein). [3H]DuP 734 binding was substantially reduced by treating the membrane with proteases and completely abolished by heat denaturation. [3H]DuP 734 binding was unaffected by the presence of ions or guanine nucleotides. The pharmacological characteristics of [3H]DuP 734 binding in cerebellum displayed the same rank order and stereospecificity as previously reported for sigma receptors in brain. [3H]DuP 734-labeled sigma receptors were heterogeneously distributed throughout the central nervous systems with highest densities present in pons/medulla, hypothalamus, spinal cord and cerebellum. In addition to labeling sigma receptors, a second, lower affinity, haloperidol-insensitive [3H] DuP 734 binding site was observed in the cerebral cortex. This second site could not be positively identified as a neuronal receptor because a series of standard compounds were unable to displace [3H]DuP 734 from the haloperidol-insensitive site; only structural analogs of DuP 734 proved effective in displacing [3H]DuP 734 from the haloperidol-insensitive site. In summary, [3H]DuP 734 is a novel ligand that binds with high affinity to sigma receptors in brain.
Culp
S G
SG
Du Pont Merck Pharmaceutical Company, Wilmington, Delaware.
Rominger
D
D
Tam
S W
SW
De Souza
E B
EB
D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism* / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D051379:Mice; D010620:Phenazocine / Q000031:analogs & derivatives / Q000378:metabolism; D010672:Phenytoin / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013696:Temperature
D014150:Antipsychotic Agents; D010880:Piperidines; D017480:Receptors, sigma; D006165:Guanylyl Imidodiphosphate; D010672:Phenytoin; C012134:SK&F 10047; C026539:preclamol; C078773:DuP 734; D010620:Phenazocine