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.