title: RTI-4793-14, a new ligand with high affinity and selectivity for the (+)-MK801-insensitive [3H]1-]1-(2-thienyl)cyclohexyl]piperidine binding site (PCP site 2) of guinea pig brain.
abstract: [3H]TCP, an analog of the dissociative anesthetic phencyclidine (PCP), binds with high affinity to two sites in guinea pig brain membranes, one that is MK-801 sensitive and one that is not. The MK-801-sensitive site (PCP site 1) is associated with NMDA receptors, whereas the MK-801-insensitive site (PCP site 2) may be associated with biogenic amine transporters (BAT). Although several "BAT ligands" are known that bind selectively to PCP site 2 and not to PCP site 1 (such as indatraline), these compounds have low affinity for site 2 (Ki values > 1 microM). Here we demonstrate that the novel pyrrole RTI-4793-14 is a selective, high affinity ligand for PCP site 2. We determined the IC50 values of RTI-4793-14 and several reference compounds [PCP, (+)-MK801 and indatraline] for PCP site 1 (assayed with [3H](+)-MK801), PCP site 2 (assayed with [3H]TCP in the presence of 500 nM (+)-MK801) and a variety of BAT-related measures ([3H]CFT binding to the DA transporter, [3H]nisoxetine binding to the norepinephrine transporter, [3H]dopamine uptake, [3H]serotonin uptake). In addition, we determined the ability of RTI-4793-14 to block NMDA responses in cultured hippocampal neurons under voltage clamp. (+)-MK801 had high affinity for PCP site 1 (4.6 nM) and potently inhibited NMDA-induced responses, but was much less potent in the BAT-related measures (IC50 s > 10 microM). PCP had high affinity at PCP site 1 (IC50 = 92 nM) and PCP site 2 (IC50 = 117 nM), and was moderately potent in all BAT-related measures except [3H]nisoxetine binding.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Clinical Psychopharmacology Section, NIDA/NIH Addiction Research Center, Baltimore, Maryland 21224.
authors.forename: C B
authors.initials: CB
authors.lastname: Goodman
authors.forename: D N
authors.initials: DN
authors.lastname: Thomas
authors.forename: A
authors.initials: A
authors.lastname: Pert
authors.forename: B
authors.initials: B
authors.lastname: Emilien
authors.forename: J L
authors.initials: JL
authors.lastname: Cadet
authors.forename: F I
authors.initials: FI
authors.lastname: Carroll
authors.forename: B E
authors.initials: BE
authors.lastname: Blough
authors.forename: S W
authors.initials: SW
authors.lastname: Mascarella
authors.forename: M A
authors.initials: MA
authors.lastname: Rogawski
authors.forename: S
authors.initials: S
authors.lastname: Subramaniam
mesh_terms: D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004594:Electrophysiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007192:Indenes / Q000378:metabolism*; D008024:Ligands; D008297:Male; D017551:Microdialysis; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000378:metabolism; D011758:Pyrroles / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017478:Receptors, Phencyclidine / Q000187:drug effects / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D015306:Biogenic Monoamines; D007192:Indenes; D008024:Ligands; D011758:Pyrroles; D017478:Receptors, Phencyclidine; C086342:RTI 4793-14; D016291:Dizocilpine Maleate; C012058:tenocyclidine; D010622:Phencyclidine