Affinity of (+/-)-pindolol, (-)-penbutolol, and (-)-tertatolol for pre- and postsynaptic serotonin 5-HT(1A) receptors in human and rat brain

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Anti-Arrhythmia Agents / pharmacokinetics*
  • Autoradiography
  • Brain / metabolism*
  • Dentate Gyrus / metabolism
  • Female
  • Hippocampus / metabolism
  • Humans
  • Male
  • Penbutolol / pharmacokinetics*
  • Pindolol / pharmacokinetics*
  • Piperazines / pharmacokinetics
  • Propanolamines / pharmacokinetics*
  • Pyridines / pharmacokinetics
  • Radioligand Assay
  • Raphe Nuclei / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Presynaptic / metabolism*
  • Receptors, Serotonin / metabolism*
  • Receptors, Serotonin, 5-HT1
  • Serotonin Antagonists / pharmacokinetics
  • Synapses / metabolism*
  • Thiophenes*
  • Tritium


  • Anti-Arrhythmia Agents
  • Piperazines
  • Propanolamines
  • Pyridines
  • Receptors, Presynaptic
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Serotonin Antagonists
  • Thiophenes
  • Tritium
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • Penbutolol
  • tertatolol
  • Pindolol