ISSN:
1471-4159
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
There is considerable interest in the use of drugs that selectively block presynaptic (somatodendritic) serotonin 5-HT1A receptors for the adjunctive treatment of major depressive disorder. The 5-HT1A/β-adrenoceptor ligands (±)-pindolol, (-)-tertatolol, and (-)-penbutolol are currently under clinical investigation, and knowledge of their affinity at different populations of central 5-HT1A receptors is needed. Here we have determined the affinity of these drugs for presynaptic and postsynaptic 5-HT1A receptors in postmortem human and rat brain using receptor autoradiography and the selective 5-HT1A radioligand [3H]WAY-100635. The binding of [3H]WAY-100635 was specific and saturable and showed high affinity in the rat dorsal raphe nucleus and hippocampus (KD = 1.5-1.7 nM). In competition studies, the three compounds had nanomolar affinity and produced monophasic displacement of [3H]WAY-100635 binding in all regions of both species. (-)-Penbutolol and (-)-tertatolol had similar affinity for pre-and postsynaptic 5-HT1A receptors in both rat and human brain. However, in the human, but not the rat, the affinity of (±)-pindolol in dorsal raphe nucleus (Ki = 8.9 ± 1.1 nM) was slightly but significantly higher than that in hippocampus (Ki = 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-HT1A receptors. (-)-Penbutolol and (-)-tertatolol do not discriminate between the pre- and postsynaptic 5-HT1A 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1046/j.1471-4159.2000.0750755.x
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