title: Magnitude of 5-HT1B and 5-HT1A receptor activation in guinea-pig and rat brain: evidence from sumatriptan dimer-mediated [35S]GTPgammaS binding responses.
abstract: The present study reports on G-protein activation by recombinant 5-HT receptors and by native 5-HT1A and 5-HT1B receptors in guinea-pig and rat brain using agonist-stimulated [35S]GTPgammaS binding responses mediated by a new 5-HT ligand, a dimer of sumatriptan. Dimerization of sumatriptan increased the binding affinity for h 5-HT1B (pKi: 9.22 vs. 7.79 for sumatriptan), h 5-HT1D (9.07 vs. 8.08) and also h 5-HT1A receptors (7.80 vs. 6.40), while the binding affinity for h 5-ht1E (6.67 vs. 6.19) and h 5-ht1F (7.37 vs. 7.78) receptors was not affected. Sumatriptan dimer (10 microM) stimulated [35S]GTPgammaS binding mainly in the superficial gray layer of the superior colliculi, hippocampus and substantia nigra of guinea-pig and rat coronal brain sections. This fits with the labelling by the 5-HT1B/1D receptor antagonist [3H] GR 125743. The observed [35S]GTPgammaS binding responses in the substantia nigra are likely to be mediated by stimulation of the 5-HT1B receptor subtype, since they were antagonized by the 5-HT1B inverse agonist SB 224289 (10 microM), and not by the 5-HT2A/1D antagonist ketanserin (10 microM). Quantitative assessment of the [35S]GTPgammaS binding responses in the substantia nigra of rat showed highly efficacious responses for both sumatriptan dimer and its monomer. In contrast, less efficacious agonist responses (51+/-10% and 35+/-13%, respectively) were measured in the guinea-pig substantia nigra. This may suggest that the G-protein coupling efficacy of 5-HT1B receptors is different between the substantia nigra of both species. In addition, the sumatriptan dimer also activated guinea-pig and rat hippocampal 5-HT1A receptors with high efficacy in contrast to sumatriptan. Therefore, dimerization of sumatriptan can be considered as a new approach to transform a partial 5-HT1A agonist into a more efficacious agonist. In conclusion, the sumatriptan dimer stimulates G-protein activation via 5-HT1B receptors besides 5-HT1A receptors in guinea-pig and rat brain. The magnitude of the 5-HT1B receptor responses is superior for sumatriptan and its dimer in rat compared to guinea-pig substantia nigra.
authors: Cellular and Molecular Biology Department, Centre de Recherche Pierre Fabre, 17, avenue Jean Moulin, F-81106, Castres cédex, France.
authors: D S
authors: DS
authors: Dupuis
authors: M
authors: M
authors: Perez
authors: S
authors: S
authors: Halazy
authors: F C
authors: FC
authors: Colpaert
authors: P J
authors: PJ
authors: Pauwels
mesh_terms: D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D019281:Dimerization; D019204:GTP-Binding Proteins / Q000502:physiology; D005910:Glioma; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism / Q000494:pharmacology*; D006153:Guanosine Diphosphate / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013462:Sulfur Radioisotopes; D018170:Sumatriptan / Q000494:pharmacology*; D014363:Tryptamines / Q000494:pharmacology
chemical_list: C470302:HTR1B protein, human; D008565:Membrane Proteins; D010069:Oxadiazoles; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D013462:Sulfur Radioisotopes; D014363:Tryptamines; C085632:L 694247; D006153:Guanosine Diphosphate; C089008:5-(nonyloxy)tryptamine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D018170:Sumatriptan; D019204:GTP-Binding Proteins