5-HT Reuptake Inhibitors with 5-HT_1B/1DAntagonistic Activity:  A New Approach toward Efficient Antidepressants

Abstract

As part of our research program toward new, potential antidepressants, a series of unsymmetrical ureas has been prepared and evaluated as 5-HT reuptake inhibitors with 5-HT(1B/1D) antagonistic activities. The design of these compounds was based on coupling of various indole derivatives, previously shown to inhibit 5-HT reuptake, to three different aniline moieties, which are part of known 5-HT(1B/1D) ligands. Binding experiments in rat frontal cortex using [(125)I]iodocyanopindolol, in calf striatum using [(3)H]5-HT, and in rat hippocampus using [(3)H]8-OH-DPAT as radioligands, respectively, revealed significantly higher affinity at the 5-HT(1B) receptor as compared to the affinities for the 5-HT(1A) and 5-HT(1D) receptors for a number of compounds, among them 4-(5-fluoro-1H-indol-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 analogue 21b. Conformational restriction of the aniline moiety in 5 only slightly enhanced the 5-HT(1B) affinity, whereas introduction of an aniline moiety with higher conformational flexibility resulted in a less potent 5-HT(1B) receptor ligand as compared to 5. The functional 5-HT(1B/1D) antagonistic activity was investigated using the rabbit saphenous vein model as well as the [(3)H]5-HT release from guinea pig cortical slices. All new compounds tested in the rabbit saphenous vein model were shown to antagonize the sumatriptan-evoked contractile responses with pA(2) values ranging from 7.3 to 8.7. These 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 [(3)H]5-HT release. The 5-HT reuptake inhibition of the ureas determined in rat brain synaptosomes was found to be either increased or decreased as compared to the uncoupled indole derivatives indicating that the reuptake inhibition shown by the ureas is not only due to the indole 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-HT(1B/1D) antagonism in vitro. This dual pharmacological profile should in theory lead to a pronounced enhancement in serotonergic neurotransmission and consequently to a more efficient treatment of depression.

5-HT1B receptors, ventral orbitofrontal cortex, and aggressive behavior in mice

“…For example, stimulation of 5-HT 1B receptors can result in a suppression of migraine (Humphrey et al 1991), an increase in locomotor activity (Rempel et al 1993;Scearce-Levie et al 1999), increased satiety (Lee and Simansky 1997), a decrease of anxiety-like behavior, increased antidepressant effects (Lucas et al 1997;Matzen et al 2000) as well as enhancement of some of the reinforcing effects of cocaine (Parsons et al 1996; but a decrease in alcohol intake (Maurel et al 1999;Tomkins and O'Neill 2000). It appears that this receptor subtype represents an important target for several potential therapeutic interventions, and it remains to be discovered whether the mechanisms for the anti-aggressive effects can be dissociated from those on other behavioral and physiological functions.…”

Role of extracellular serotonin levels in the effect of 5-HT1B receptor blockade

“…The effect of systemic SSRIs on 5-HT levels are augmented by 5-HT 1B receptor antagonists in the frontal cortex (Gobert et al 1997(Gobert et al , 2000Dawson and Nguyen 2000) and other brain areas (Rollema et al 1996;Cremers et al 2000). Compounds that act both as a SSRI and 5-HT 1B receptor antagonist have been found to potently enhance 5-HT levels (Matzen et al 2000;Mitchell 2001). Furthermore, a limiting role of 5-HT 1B autoreceptors in the effect of SSRIs on cortical 5-HT levels is supported by recent findings in mice lacking 5-HT 1B receptors (Malagie et al 2001;de Groote et al 2002).…”

[N-methyl-3H3]AZ10419369 Binding to the 5-HT1BReceptor: In Vitro Characterization and in Vivo Receptor Occupancy

“…5-HT 1B receptors modulate synaptic release of sero-tonin (Hoyer et al, 2002) acting as autoreceptors on serotoninergic terminals or as heteroreceptors on non-serotonergic neurons (Engel et al, 1986;Sari et al, 1999;Roberts et al, 2001;Sari, 2004). Blocking 5-HT 1B autoreceptors with a selective ligand increases extracellular levels of 5-HT and has an additive effect on 5-HT increase when combined with selective serotonin reuptake inhibitors, suggesting the antidepressive potential of a 5-HT 1B drug (Matzen et al, 2000;Smagin et al, 2003). Indeed, drugs targeting 5-HT 1B receptors have shown efficacy in animal models of depression and anxiety (Hudzik et al, 2003a,b;Dawson et al, 2006).…”