Wash-resistant inhibition of phencyclidine- and haloperidol-sensitive sigma receptor sites in guinea pig brain by putative affinity ligands: Determination of selectivity

Several putative affinity ligands, based on the structures of phencyclidine etoxadrol, 5-methyl-10, 11-dihydro-5H-dibenzo[a,d] cycloheptene-5,10-imine (MK801) and 1,3-di-(2-methylphenyl)guanidine (DTG) were evaluated in vitro for their ability to produce a wash-resistant inhibition of phencyclidine and sigma receptor sites in homogenates of the brain of the guinea pig. All the phencyclidine-based ligands, including 1-[1-(3-isothiocyanatophenyl)cyclohexyl]piperidine (Metaphit) and (±)- N-(2-isothiocyanato-ethyl) MK801 [(±)-MK801-NCS], produced a wash-resistant inhibition of binding sites for phencyclidine, labelled by [ 3H]-1-[1-(2-thienyl)cyclohexyl]piperidine ([ 3H]TCP) and sigma binding sites, labelled by [ 3H]DTG. The DTG-based ligands, 1-(4-isothiocyanato-2-methylphenyl)-3-(2-methylphenyl)guanidine (DIGIT) and 1-4-[2-(2-isothiocyanatoethoxy)ethoxy]-2-methyl-phenyl-3-(2-methylphenyl)guanidine (DIGIE), produced a wash-resistant inhibition of sigma sites, at concentrations as small as 1 μM and also inhibited binding sites for phencyclidine at larger concentrations (100 μM). Both 1-(3-isothiocyanatophenyl)-1-ethyl-4-(2-piperidyl)-1, 3-dioxolane(ETOX-NCS)and 1-[1-(3-bromoacetyloxyphenyl)cyclohexyl]-1,2,3,6-tetrahydropyridine (Bromoacetyl-PCP) were the most potent and selective inhibitors of the binding of [ 3H]TCP, while DIGIT was the most selective inhibitor of the binding of [ 3H]DTG. Future studies will examine the selectivity of these agents in vivo after intracerebroventricular administration.