SB-272183, a selective 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptor antagonist in native tissue

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-HT(1A), 5-HT(1B) and 5-HT(1D) receptors with pK(i) values of 8.0, 8.1 and 8.7 respectively and is at least 30 fold selective over a range of other receptors. [(35)S]-GTPgammaS binding studies showed that SB-272183 acts as a partial agonist at human recombinant 5-HT(1A), 5-HT(1B) and 5-HT(1D) 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 [(35)S]-GTPgammaS binding at human 5-HT(1A) and 5-HT(1B) receptors to give pA(2) values of 8.2 and 8.5 respectively. However, from [(35)S]-GTPgammaS autoradiographic studies in rat and human dorsal raphe nucleus, SB-272183 did not display intrinsic activity up to 10 microM but did block 5-HT-induced stimulation of [(35)S]-GTPgammaS binding. From electrophysiological studies in rat raphe slices in vitro, SB-272183 did not effect cell firing rate up to 1 microM but was able to attenuate (+)8-OH-DPAT-induced inhibition of cell firing to give an apparent pK(b) of 7.1. SB-272183 potentiated electrically-stimulated [(3)H]-5-HT release from rat and guinea-pig cortical slices at 100 and 1000 nM, similar to results previously obtained with the 5-HT(1B) and 5-HT(1D) receptor antagonist, GR127935. 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 pK(b) of 7.2, but did not effect basal efflux up to 1 microM. These studies show that, in vitro, SB-272183 acts as an antagonist at native tissue 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors.