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.
C B Goodman, D N Thomas, A Pert, B Emilien, J L Cadet, F I Carroll, B E Blough, S W Mascarella, M A Rogawski, S Subramaniam
Synapse (New York, N.Y.) January 1, 1994 DOI: 10.1002/syn.890160107 (opens in new tab) via PubMed
Summary
AI-generated from the abstractThe novel compound RTI-4793-14 binds selectively and with high affinity to a brain site (PCP site 2) that is insensitive to MK-801 and may be associated with biogenic amine transporters. In contrast, MK-801 binds with high affinity only to PCP site 1 (associated with NMDA receptors) and potently blocks NMDA responses, while PCP binds with high affinity to both sites and is moderately potent across several transporter-related measures. RTI-4793-14 is the first selective, high-affinity ligand for PCP site 2.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Guinea pig brain membranes and cultured hippocampal neurons |
| Interventions | RTI-4793-14 PCP (+)-MK801 indatraline |
| Key finding | RTI-4793-14 is a selective, high-affinity ligand for the MK-801-insensitive PCP site 2, unlike other known compounds. |
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)