2--hydroxy-5-9-dimethyl-2-allyl-6-7-benzomorphan and 3-hydroxyphencyclidine

The effect of guanine nucleotides and ions on (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [+ )-[3H]3-PPP), (+)-N-[3H]allylnormetazocine ((+)-[3H]SKF 10047) and [3H]1-[1-(3-hydroxyphenyl)-cyclohexyl]piperidine ([3H]PCP-3-OH) specific binding to rat brain membranes was examined. These 3 compounds are proposed as prototypical ligands for the labeling of the sigma- and phencyclidine (PCP)-receptor subtypes. Competition binding experiments of (+)-SKF 10047 with (+)-[3H]3-PPP yielded a biphasic inhibition curve which transformed to a monophasic curve when membranes were incubated in the presence of Gpp(NH)p (0.1 mM). The common (+)-[3H]3-PPP/(+)-SKF 10047 binding component is more susceptible to Gpp(NH)p than the high affinity [3H]PCP-3-OH/(+)-SKF 10047 common binding component. Low affinity [3H]PCP-3-OH binding, which may represent a PCP-selective site, is not affected by GTP and Gpp(NH)p. Mono- and divalent cations markedly inhibit high affinity [3H]PCP-3-OH binding but they had a differential inhibitory effect on the binding of the other radioligands tested. These findings suggest differences in the regulation of multiple psychotomimetic (sigma- and PCP) binding sites by guanine nucleotides and ions.

Topics: Animals; Binding, Competitive; Brain; Cations; Guanine Nucleotides; Male; Phenazocine; Phencyclidine; Piperidines; Rats; Receptors, Neurotransmitter; Receptors, Phencyclidine; Subcellular Fractions

The pharmacological specificity of representative psychotomimetic agents such as phencyclidine (PCP) analogs, opiate benzomorphans and several antipsychotic agents was assessed for the sigma and PCP binding sites. In a series of binding experiments, in rat brain membranes, sigma and PCP binding sites were labeled with [3H]-1-[1-(3-hydroxyphenyl)cyclohexyl]piperidine [( 3H]PCP-3-OH), (+) [3H]-N-allylnormetazocine [(+) [3H]SKF 10047] and (+) [3H]-3-[3-hydroxy-phenyl]-N-(1-propyl)piperidine [(+) [3H]-3-PPP]. PCP analogs inhibit potently high affinity [3H]PCP-3-OH binding and (+) [3H]SKF 10047 binding, moderately the low affinity binding component of [3H]PCP-3-OH and very weakly (+) [3H]-3-PPP binding. (+)SKF 10047 and cyclazocine are potent to moderate inhibitors of (+) [3H]SKF 10047, high affinity [3H]PCP-3-OH and (+) [3H]-3-PPP binding, but extremely weak inhibitors of low affinity [3H]PCP-3-OH binding. The antipsychotic agents display high affinity for (+) [3H]-3-PPP binding sites, moderate affinity for (+) [3H]SKF 10047 sites and have no effect on either the high or low affinity [3H]PCP-3-OH binding. The present data further support the existence of multiple sigma and PCP binding sites.

Topics: Animals; Antipsychotic Agents; Binding, Competitive; Haloperidol; In Vitro Techniques; Male; Phenazocine; Phencyclidine; Piperidines; Psychotropic Drugs; Rats; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma

Specific binding of one of the most potent analogs of phencyclidine (PCP), [3H]PCP-3-OH, in rat brain membranes revealed the labeling of high (Kd = 0.5 nM) and low (Kd = 16 nM) affinity binding sites. (+)SKF 10047 potently inhibited high, but not low, affinity [3H]PCP-3-OH binding. (+)[3H]SKF 10047 apparently labeled the high affinity PCP-3-OH binding site and also an additional site, sensitive to haloperidol, which is distinct from the two sites labeled by [3H]PCP-3-OH.

Topics: Animals; Binding Sites; Binding, Competitive; Brain; Haloperidol; In Vitro Techniques; Phenazocine; Phencyclidine; Rats; Receptors, Neurotransmitter; Receptors, Phencyclidine