title: Affinity of (+/-)-pindolol, (-)-penbutolol, and (-)-tertatolol for pre- and postsynaptic serotonin 5-HT(1A) receptors in human and rat brain.
abstract: 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.
authors.affiliation: University Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford, England.
authors.forename: M E
authors.initials: ME
authors.lastname: Castro
authors.forename: P J
authors.initials: PJ
authors.lastname: Harrison
authors.forename: A
authors.initials: A
authors.lastname: Pazos
authors.forename: T
authors.initials: T
authors.lastname: Sharp
mesh_terms: D000368:Aged; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics*; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D018891:Dentate Gyrus / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D010394:Penbutolol / Q000493:pharmacokinetics*; D010869:Pindolol / Q000493:pharmacokinetics*; D010879:Piperazines / Q000493:pharmacokinetics; D011412:Propanolamines / Q000493:pharmacokinetics*; D011725:Pyridines / Q000493:pharmacokinetics; D011869:Radioligand Assay; D011903:Raphe Nuclei / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017661:Receptors, Presynaptic / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000493:pharmacokinetics; D013569:Synapses / Q000378:metabolism*; D013876:Thiophenes; D014316:Tritium
chemical_list: D000889:Anti-Arrhythmia Agents; D010879:Piperazines; D011412:Propanolamines; D011725:Pyridines; D017661:Receptors, Presynaptic; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D013876:Thiophenes; D014316:Tritium; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D010394:Penbutolol; C005632:tertatolol; D010869:Pindolol