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 (K(i) values > 1 μM). 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 (IC50s > 10 μM). 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. Indatraline was potent in BAT-related measures (IC50s, 2 to 5 nM), but weak in other measures (IC50s > 1 μM). In contrast, RTI-4793-14 had high affinity for PCP site 2 (38 nM), low affinity for PCP site 1 (> 36 μM), moderate IC50s for all BAT-related measures, and negligible activity at NMDA receptors. Viewed collectively, these data indicate that RTI-4793-14 binds with high affinity and selectivity to PCP site 2 and provide further support for an association between PCP site 2 and the BATs.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 59-65 |
| Number of pages | 7 |
| Journal | Synapse |
| Volume | 16 |
| Issue number | 1 |
| DOIs | |
| State | Published - 1994 |
| Externally published | Yes |
Fingerprint
Keywords
- (+)-MK801
- Biogenic amine reuptake carrier
- Guinea pig brain
- PCP
- Phencyclidine receptor
- RTI-4793-14
ASJC Scopus subject areas
- Neuroscience(all)
- Physiology
- Pharmacology
Cite this
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. / Goodman, C. B.; Thomas, D. N.; Pert, A.; Emilien, B.; Cadet, J. L.; Carroll, F. I.; Blough, B. E.; Mascarella, S. W.; Rogawski, Michael A; Subramaniam, S.; Rothman, R. B.
In: Synapse, Vol. 16, No. 1, 1994, p. 59-65.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
AU - Goodman, C. B.
AU - Thomas, D. N.
AU - Pert, A.
AU - Emilien, B.
AU - Cadet, J. L.
AU - Carroll, F. I.
AU - Blough, B. E.
AU - Mascarella, S. W.
AU - Rogawski, Michael A
AU - Subramaniam, S.
AU - Rothman, R. B.
PY - 1994
Y1 - 1994
N2 - [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 (K(i) values > 1 μM). 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 (IC50s > 10 μM). 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. Indatraline was potent in BAT-related measures (IC50s, 2 to 5 nM), but weak in other measures (IC50s > 1 μM). In contrast, RTI-4793-14 had high affinity for PCP site 2 (38 nM), low affinity for PCP site 1 (> 36 μM), moderate IC50s for all BAT-related measures, and negligible activity at NMDA receptors. Viewed collectively, these data indicate that RTI-4793-14 binds with high affinity and selectivity to PCP site 2 and provide further support for an association between PCP site 2 and the BATs.
AB - [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 (K(i) values > 1 μM). 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 (IC50s > 10 μM). 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. Indatraline was potent in BAT-related measures (IC50s, 2 to 5 nM), but weak in other measures (IC50s > 1 μM). In contrast, RTI-4793-14 had high affinity for PCP site 2 (38 nM), low affinity for PCP site 1 (> 36 μM), moderate IC50s for all BAT-related measures, and negligible activity at NMDA receptors. Viewed collectively, these data indicate that RTI-4793-14 binds with high affinity and selectivity to PCP site 2 and provide further support for an association between PCP site 2 and the BATs.
KW - (+)-MK801
KW - Biogenic amine reuptake carrier
KW - Guinea pig brain
KW - PCP
KW - Phencyclidine receptor
KW - RTI-4793-14
UR - http://www.scopus.com/inward/record.url?scp=0028089028&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0028089028&partnerID=8YFLogxK
U2 - 10.1002/syn.890160107
DO - 10.1002/syn.890160107
M3 - Article
C2 - 8134901
AN - SCOPUS:0028089028
VL - 16
SP - 59
EP - 65
JO - Synapse
JF - Synapse
SN - 0887-4476
IS - 1
ER -