SB-272183 a selective 5-HT1A 5-HT1B and 5-HT1D receptor antagonist in native tissue

摘要

class="enumerated" style="list-style-type:decimal">A novel compound, SB-272183 (5-Chloro-2, 3-dihydro-6-[4-methylpiperazin-1-yl]-1[4-pyridin-4-yl]napth-1-ylaminocarbonyl]-1H-indole), has been shown to have high affinity for human 5-HT1A, 5-HT1B and 5-HT1D receptors with pKi values of 8.0, 8.1 and 8.7 respectively and is at least 30 fold selective over a range of other receptors.[³⁵S]-GTPγS binding studies showed that SB-272183 acts as a partial agonist at human recombinant 5-HT1A, 5-HT1B and 5-HT1D receptors with intrinsic activities of 0.4, 0.4 and 0.8 respectively, compared to 5-HT. SB-272183 inhibited 5-HT-induced stimulation of [³⁵S]-GTPγS binding at human 5-HT1A and 5-HT1B receptors to give pA2 values of 8.2 and 8.5 respectively. However, from [³⁵S]-GTPγS autoradiographic studies in rat and human dorsal raphe nucleus, SB-272183 did not display intrinsic activity up to 10 μM but did block 5-HT-induced stimulation of [³⁵S]-GTPγS binding.From electrophysiological studies in rat raphe slices in vitro, SB-272183 did not effect cell firing rate up to 1 μM but was able to attenuate (+)8-OH-DPAT-induced inhibition of cell firing to give an apparent pKb of 7.1.SB-272183 potentiated electrically-stimulated [³H]-5-HT release from rat and guinea-pig cortical slices at 100 and 1000 nM, similar to results previously obtained with the 5-HT1B and 5-HT1D receptor antagonist, .Fast cyclic voltammetry studies in rat dorsal raphe nucleus showed that SB-272183 could block sumatriptan-induced inhibition of 5-HT efflux, with an apparent pKb of 7.2, but did not effect basal efflux up to 1 μM.These studies show that, in vitro, SB-272183 acts as an antagonist at native tissue 5-HT1A, 5-HT1B and 5-HT_1D receptors.