title: Effects of selective h5-HT1B (SB-216641) and h5-HT1D (BRL-15572) receptor ligands on guinea-pig and human 5-HT auto- and heteroreceptors.
abstract: Human cerebral cortical slices and synaptosomes, guinea-pig cerebral cortical slices and human right atrial appendages were used to study the effects of SB-216641, a preferential h5-HT1B receptor ligand, and of BRL-15572, a preferential h5-HT1D receptor ligand, on the presynaptic h5-HT1B and h5-HT1B-like autoreceptors in the human and guinea-pig brain preparations, respectively, and on the presynaptic h5-HT1D heteroreceptors in the human atrium. The brain preparations, preincubated with [3H]serotonin ([3H]5-HT), and the segments of atrial appendages, preincubated with [3H]noradrenaline, were superfused with modified Krebs' solution and tritium overflow was evoked electrically (human and guinea-pig cerebral cortex slices and human atrial appendages) or by high K+ (human cerebral cortex synaptosomes). The electrically evoked tritium overflow from guinea-pig cerebral cortex slices was reduced by the 5-HT receptor agonist 5-carboxamidotryptamine (5-CT). This effect was not modified by BRL-15572 (2 microM; concentration 154 times higher than its Ki at h5-HT1D receptors) but was antagonized by SB-216641 (0.1 microM; concentration 100 times higher than its Ki at h5-HT1B receptors; apparent pA2 8.45). SB-216641 (0.1 microM) by itself facilitated, whereas BRL-15572 (2 microM) did not affect, the evoked overflow. In human cerebral cortex slices SB-216641 (0.1 microM) also facilitated, and BRL-15572 (2 microM) again failed to affect, the electrically evoked tritium overflow. In human cerebral cortical synaptosomes, 5-CT reduced the K+-evoked tritium overflow. This response was unaffected by BRL-15572 (300 nM) but antagonized by SB-216641 (15 nM; drug concentrations 23 and 15 times higher than their Ki at h5-HT1D and h5-HT1B receptors, respectively). Both drugs, given alone, did not modify the K+-evoked tritium overflow. In human atrial appendages, the electrically evoked tritium overflow was inhibited by 5-HT in a manner susceptible to antagonism by BRL-15572 (300 nM; 23 times Ki at h5-HT1D receptors) but not by SB-216641 (30 nM; 30 times Ki at h5-HT1B receptors). Both drugs by themselves did not change the electrically evoked tritium overflow. In conclusion, SB-216641 behaves as a preferential antagonist at native human 5-HT1B receptors and BRL-15572 as a preferential antagonist at native human 5-HT1D receptors. These compounds are clearly useful tools for the differentiation between human 5-HT1B and 5-HT1D receptors in functional studies.
authors.affiliation: Institut für Pharmakologie und Toxikologie, Universität Bonn, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Schlicker
authors.forename: K
authors.initials: K
authors.lastname: Fink
authors.forename: G J
authors.initials: GJ
authors.lastname: Molderings
authors.forename: G W
authors.initials: GW
authors.lastname: Price
authors.forename: M
authors.initials: M
authors.lastname: Duckworth
authors.forename: L
authors.initials: L
authors.lastname: Gaster
authors.forename: D N
authors.initials: DN
authors.lastname: Middlemiss
authors.forename: J
authors.initials: J
authors.lastname: Zentner
authors.forename: J
authors.initials: J
authors.lastname: Likungu
authors.forename: M
authors.initials: M
authors.lastname: Göthert
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D004558:Electric Stimulation; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D010069:Oxadiazoles / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014316:Tritium
chemical_list: D017660:Autoreceptors; D001549:Benzamides; D001713:Biphenyl Compounds; C470302:HTR1B protein, human; D008024:Ligands; C108531:N-(3-(2-dimethylamino)ethoxy-4-methoxyphenyl)-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide; D010069:Oxadiazoles; D010879:Piperazines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D014316:Tritium; D012701:Serotonin; C108532:BRL 15572; D011188:Potassium