5-HT reuptake inhibitors with 5-HT1B/1D antagonistic activity: A new approach toward efficient antidepressants

As part of our research program toward new, potential antidepressants, a se ries of unsymmetrical ureas has been prepared and evaluated as 5-HT reuptak e inhibitors with 5-HT1B/1D antagonistic activities. The design of these co mpounds was based on coupling of various indole derivatives, previously sho wn to inhibit 5-HT reuptake, to three different aniline moieties, which are part of known 5-HT1B/1D ligands. Binding experiments in rat frontal cortex using [I-125]iodocyanopindolol, in calf striatum using [H-3]5-HT, and in r at hippocampus using [H-3]8-OH-DPAT as radioligands, respectively, revealed significantly higher affinity at the 5-HT1B receptor as compared to the af finities for the 5-HT1A and 5-HT1D receptors for a number of compounds, amo ng them 4-(5-fluoro-1H-indolyl-3-yl)piperidine-1-carboxylic acid [4-methoxy -3-(4-methylpiperazin-1-yl)phenyl]amide (5), the corresponding 4-fluoro-1H- indol-3-yl analogue 21a, and the corresponding 6-fluoro-1H-indol-3-yl analo gue 21b. Conformational restriction of the aniline moiety in 5 only slightl y enhanced the 5-HT1B affinity, whereas introduction of an aniline moiety w ith higher conformational flexibility resulted in a less potent 5-HT1B rece ptor ligand as compared to 5. The functional 5-HT1B/1D antagonistic activit y was investigated using the rabbit saphenous vein model as well as the [H- 3]5-HT release from guinea pig cortical slices. All new compounds tested in the rabbit saphenous vein model were shown to antagonize the sumatriptan-e voked contractile responses with pA(2) values ranging from 7.3 to 8.7. Thes e observations were consistent with the results of the cortical slice model , in which the ureas were found to block the sumatriptan-induced inhibition of potassium-evoked [H-3]5-HT release. The 5-HT reuptake inhibition of the ureas determined in rat brain synaptosomes was found to be either increase d or decreased as compared to the uncoupled indole derivatives indicating t hat the reuptake inhibition shown by the ureas is not only due to the indol e part but also affected by the aniline moiety of the molecule. Among this series of compounds described the ureas 5, 21a, and 21b seem to be the most interesting candidates showing both 5-HT reuptake inhibition and 5-HT1B/1D antagonism in vitro. This dual pharmacological profile should in theory le ad to a pronounced enhancement in serotonergic neurotransmission and conseq uently to a more efficient treatment of depression.