Binding profile of the novel 5-HT1B/1D receptor antagonist, [3H]GR 125,743, in guinea-pig brain: a comparison with [3H]5-carboxamidotryptamine.
Native brain 5-HT1B/1D) receptors were studied using the novel antagonist, [3H]GR 125,743 (N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-pyri dyl)benzamide). In guinea-pig striatal membranes, [3H]GR 125,743 displayed rapid association (t1/2 = 4.5 min), high (90%) specific binding and high affinity (K(d) = 0.29 nM), although B(max) values (fmol/mg protein) varied according to brain region-striatum: 199; frontal cortex: 89; hippocampus: 79; cerebellum: 26. In frontal cortex, the B(max) determined with [3H]5-CT ([3H]carboxamidotryptamine) was significantly higher (178; P < 0.05), suggesting that it also labels other binding sites. In striatal membranes, guanylylimidodiphosphate (GppNHp) inhibited [3H]5-CT but not [3H]GR 125,743 binding, suggesting that the latter has antagonist properties. Nevertheless, in competition binding experiments, the pK(i) values obtained with [3H]GR 125,743 and [3H]5-CT for 20 serotonergic ligands, including L 694,247 (2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl ]-1H-indole-3-yl]ethylamine), GR46,611 (3-[3-(2-dimethylamino-ethyl)-1H-indol-6-yl]-N-(4-methoxybenzyl)acrylami de), sumatriptan and alniditan, were highly correlated (r = 0.99). Ketanserin and ritanserin showed low affinity for [3H]GR 125,743 binding to guinea-pig striatal sites (K(i) = 12600 and 369 nM), suggesting that 5-HT1B (rather than 5-HT1D) receptors are predominantly labelled in this tissue. The present data indicate that [3H]GR 125,743 is a useful tool for studying native 5-HT1B/1D receptors.
Audinot
V
V
Institut de Recherches Servier, Department of Psychopharmacology, Croissy-sur-Seine, France.
Lochon
S
S
Newman-Tancredi
A
A
Lavielle
G
G
Millan
M J
MJ
D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics*; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D006168:Guinea Pigs; D007700:Kinetics; D011725:Pyridines / Q000493:pharmacokinetics*; D012701:Serotonin / Q000031:analogs & derivatives* / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000378:metabolism*
D001549:Benzamides; C107225:N-(4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)-3-methyl-4-(4-pyridyl)benzamide; D011725:Pyridines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C047087:5-carboxamidotryptamine