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

• Published in: British journal of pharmacology 2001-07, Vol.133 (6), p.797-806
• Main Authors: Watson, J, Roberts, C, Scott, C, Kendall, I, Collin, L, Day, N C, Harries, M H, Soffin, E, Davies, C H, Randall, A D, Heightman, T, Gaster, L, Wyman, P, Parker, C, Price, G W, Middlemiss, D N
• Format: Article
• Language: English
• Subjects: 5‐HT1A; 5‐HT1B; 5‐HT1D receptors; Biological and medical sciences; guinea‐pig; human; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; rat; recombinant cells; SB‐272183; Serotoninergic system
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0704133

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, 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 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‐HT1D receptors. British Journal of Pharmacology (2001) 133, 797–806; doi:10.1038/sj.bjp.0704133