title: Wash-resistant inhibition of phencyclidine- and haloperidol-sensitive sigma receptor sites in guinea pig brain by putative affinity ligands: determination of selectivity.
abstract: 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-isothiocyanatoethyl) 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 microM and also inhibited binding sites for phencyclidine at larger concentrations (100 microM). Both 1-(3-isothiocyanatophenyl)-1-ethyl-4-(2-piperidyl)-1,3-dioxolane (ETOX-NCS) and 1-[1-(3-bromoacetyloxyphenyl)cyclohexyl]-1,2,3,6-tetrahydropyri din e (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.
authors.affiliation: Laboratory of Medicinal Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892.
authors.forename: A A
authors.initials: AA
authors.lastname: Reid
authors.forename: C H
authors.initials: CH
authors.lastname: Kim
authors.forename: A
authors.initials: A
authors.lastname: Thurkauf
authors.forename: J A
authors.initials: JA
authors.lastname: Monn
authors.forename: B
authors.initials: B
authors.lastname: de Costa
authors.forename: A E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: K C
authors.initials: KC
authors.lastname: Rice
authors.forename: W D
authors.initials: WD
authors.lastname: Bowen
authors.forename: R B
authors.initials: RB
authors.lastname: Rothman
mesh_terms: D000345:Affinity Labels / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D006168:Guinea Pigs; D006220:Haloperidol / Q000494:pharmacology*; D007700:Kinetics; D008024:Ligands; D008566:Membranes / Q000378:metabolism; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma
chemical_list: D000345:Affinity Labels; D008024:Ligands; D017981:Receptors, Neurotransmitter; D011957:Receptors, Opioid; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; D016291:Dizocilpine Maleate; D010622:Phencyclidine; D006220:Haloperidol