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.
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.
复制标题
RTI-4793-14，一种新配体，对豚鼠脑的 ( )-MK801 不敏感 [3H]1-]1-(2-噻吩基)环己基]哌啶结合位点（PCP 位点 2）具有高亲和力和选择性。
DOI：
10.1002/syn.890160107
复制
发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Subramaniam,S
中科院分区：
文献类型：
--
作者：
Goodman,CB;Thomas,DN;Pert,A;Emilien,B;Cadet,JL;Carroll,FI;Blough,BE;Mascarella,SW;Rogawski,MA;Subramaniam,S
[3 H]TCP是一种解离性麻醉剂苯环利定（PCP）的类似物，以高亲和力与豚鼠脑细胞膜中的两个位点结合，一个对MK-801敏感，另一个不敏感。MK-801敏感位点（PCP位点1）与NMDA受体相关，而MK-801不敏感位点（PCP位点2）可能与生物胺转运蛋白（BAT）相关。尽管已知有几种“BAT配体”选择性地与PCP位点2结合而不与PCP位点1结合（如茚达曲林），但这些化合物对位点2的亲和力较低（Ki值> 1 μ）。在这里，我们证明了新型吡咯RTI-4793 - 14是PCP位点2的选择性高亲和力配体。我们测定了RTI-4793 - 14和几种参比化合物[PCP、（+）-MK 801和茚达曲林]对PCP位点1的IC 50值（用[3 H]（+）-MK 801测定），PCP位点2（在存在500 nM（+）-MK 801的情况下用[3 H]TCP测定）和各种BAT相关测量（[3 H]CFT与DA转运蛋白结合，[3 H]尼索西汀与去甲肾上腺素转运蛋白结合，[3 H]多巴胺摄取，[3 H]血清素摄取）。此外，我们还测定了RTI-4793 - 14在电压钳下阻断培养的海马神经元中NMDA反应的能力。（+）-MK 801对PCP位点1具有高亲和力（4.6 nM），并有效抑制NMDA诱导的反应，但在BAT相关测量中的效力要低得多（IC 50> 10 μ）。PCP对PCP位点1（IC 50 = 92 nM）和PCP位点2（IC 50 = 117 nM）具有高亲和力，并且在除[3 H]尼索西汀结合外的所有BAT相关测量中具有中等效力。茚达曲林在BAT相关测量中是有效的（IC 50，2至5 nM），但在其他测量中较弱（IC 50> 1 μ）。相比之下，RTI-4793 - 14对PCP位点2具有高亲和力（38 nM），对PCP位点1具有低亲和力（> 36 μ），对所有BAT相关指标具有中等IC 50，对NMDA受体的活性可忽略不计。综合来看，这些数据表明RTI-4793 - 14以高亲和力和选择性与PCP位点2结合，并进一步支持PCP位点2与BAT之间的关联。© 1994 Wiley利斯公司
[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 (Kivalues > 1 μ). Here we demonstrate that the novel pyrrole RTI‐4793‐14 is a selective, high affinity ligand for PCP site 2. We determined the IC50values 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 μ). 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 μ). In contrast, RTI‐4793‐14 had high affinity for PCP site 2 (38 nM), low affinity for PCP site 1 (> 36 μ), 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. © 1994 Wiley‐Liss, Inc.