RS-056812-198: partial agonist on native and antagonist on cloned 5-HT3 receptors.
Effects of (R)-N-(quinuclidin-3-yl)-2-(1-methyl-1 H-indol-3-yl)-2-oxo-acetamide (RS-056812-198) on 5-HT3 receptors have been investigated in whole-cell voltage-clamped N1E-115 mouse neuroblastoma cells and on 5-HT3 receptors composed of either long (5-HT3R-Al) or short (5-HT3R-AS) subunits expressed in Xenopus laevis oocytes. In N1E-115 cells RS-056812-198 evokes small transient inward currents, which are completely and reversibly inhibited by the selective 5-HT3 receptor antagonist MDL 72222 and cross-desensitizes with the 5-hydroxytryptamine (5-HT)-evoked current. The concentration-effect curve of RS-056812-198 yields an EC50 of 18 nM and a maximum amplitude of 15% of the maximum 5-HT-evoked current. In contrast to its effects on N1E-115 cells, RS-056812-198 does not evoke an ion current on cloned 5-HT3 receptors expressed in Xenopus oocytes, but acts as an antagonist. For 5-HT3R-A1 receptors, the IC50 of RS-056812-198 is 0.4 nM. The results show that (I) RS-056812-198 is a high-affinity partial agonist on 5-HT3 receptors in N1E-115 cells, thus providing a valuable tool to study agonist-receptor interaction in more detail: (2) 5-HT3 receptors on N1E-115 cells differ from the homo-oligomeric 5-HT3 receptors expressed in Xenopus oocytes. Whether the difference is caused by differences in protein processing in the two preparations or by expression of additional, yet unidentified subunits in N1E-115 cells and consequent formation of hetero-oligomeric 5-HT3 receptors remains to be determined.
Van Hooft
J A
JA
Research Institute of Toxicology, Utrecht University, Netherlands. h.vanhooft@ritox.dgk.ruu.nl
Vijverberg
H P
HP
D000818:Animals; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D011812:Quinuclidines / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects; D044406:Receptors, Serotonin, 5-HT3; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014982:Xenopus laevis
D011812:Quinuclidines; C105631:RS 56812; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists