Castro M E, Harrison P J, Pazos A, Sharp T
University Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford, England.
J Neurochem. 2000 Aug;75(2):755-62. doi: 10.1046/j.1471-4159.2000.0750755.x.
There is considerable interest in the use of drugs that selectively block presynaptic (somatodendritic) serotonin 5-HT(1A) receptors for the adjunctive treatment of major depressive disorder. The 5-HT(1A)/beta-adrenoceptor ligands (+/-)-pindolol, (-)-tertatolol, and (-)-penbutolol are currently under clinical investigation, and knowledge of their affinity at different populations of central 5-HT(1A) receptors is needed. Here we have determined the affinity of these drugs for presynaptic and postsynaptic 5-HT(1A) receptors in postmortem human and rat brain using receptor autoradiography and the selective 5-HT(1A) radioligand [(3)H]WAY-100635. The binding of [(3)H]WAY-100635 was specific and saturable and showed high affinity in the rat dorsal raphe nucleus and hippocampus (K(D) = 1.5-1.7 nM). In competition studies, the three compounds had nanomolar affinity and produced monophasic displacement of [(3)H]WAY-100635 binding in all regions of both species. (-)-Penbutolol and (-)-tertatolol had similar affinity for pre-and postsynaptic 5-HT(1A) receptors in both rat and human brain. However, in the human, but not the rat, the affinity of (+/-)-pindolol in dorsal raphe nucleus (K(i) = 8.9 +/- 1. 1 nM) was slightly but significantly higher than that in hippocampus (K(i) = 14.4 +/- 1.5 nM in CA1). In summary, our data show that (+/-)-pindolol, (-)-tertatolol, and (-)-penbutolol are all high-affinity ligands at native human and rat 5-HT(1A) receptors. (-)-Penbutolol and (-)-tertatolol do not discriminate between the pre- and postsynaptic 5-HT(1A) sites tested in either species, but (+/-)-pindolol showed a slightly higher affinity for the presynaptic site in human brain. Further work is needed to establish whether the latter difference is clinically relevant.
对于使用能选择性阻断突触前（躯体树突）5-羟色胺5-HT(1A)受体的药物辅助治疗重度抑郁症，人们有着浓厚的兴趣。5-HT(1A)/β-肾上腺素能受体配体(±)-吲哚洛尔、(-)-替他洛尔和(-)-喷布洛尔目前正在进行临床研究，因此需要了解它们对不同中枢5-HT(1A)受体群体的亲和力。在此，我们使用受体放射自显影技术和选择性5-HT(1A)放射性配体[(3)H]WAY-100635，测定了这些药物对死后人类和大鼠大脑中突触前和突触后5-HT(1A)受体的亲和力。[(3)H]WAY-100635的结合具有特异性和饱和性，并且在大鼠背侧中缝核和海马体中显示出高亲和力（解离常数K(D)=1.5 - 1.7 nM）。在竞争研究中，这三种化合物具有纳摩尔亲和力，并且在两个物种的所有区域都能使[(3)H]WAY-100635的结合产生单相位移。(-)-喷布洛尔和(-)-替他洛尔对大鼠和人类大脑中突触前和突触后5-HT(1A)受体的亲和力相似。然而，在人类而非大鼠中，(±)-吲哚洛尔在背侧中缝核中的亲和力（抑制常数K(i)=8.9±1.1 nM）略高于但显著高于海马体CA1区中的亲和力（K(i)=14.4±1.5 nM）。总之，我们的数据表明，(±)-吲哚洛尔、(-)-替他洛尔和(-)-喷布洛尔都是天然人类和大鼠5-HT(1A)受体的高亲和力配体。(-)-喷布洛尔和(-)-替他洛尔在两个物种中测试的突触前和突触后5-HT(1A)位点之间没有差异，但(±)-吲哚洛尔对人类大脑中的突触前位点显示出略高的亲和力。需要进一步的研究来确定后一种差异是否具有临床相关性。
