SB271046

SB-271046 is a selective and orally active 5-HT6 receptor antagonist.

5-HT6 belongs to GPCR which stimulates adenylate cyclase via Gs, which cloned from rat striatum.

SB-271046 substituted [125I]-SB-258585 and [3H]-LSD from human 5-HT6 receptors which recombinantly expressed in HeLa cells in vitro (pKi 8.92 and 9.09 respectively). SB-271046 also transfered [125I]-SB-258585 from human caudate putamen and rat and pig striatum membranes (pKi 8.81, 9.02 and 8.55 respectively). By 5-HT alone or after increasing concentrations of SB-271046 (10, 30, 100 and 300 nM) stimulates adenylyl cyclase activity in HeLa cells stably expressing human 5-HT6 receptors. [1]

The affinities of SB-271046 in human (pKi 8.81), pig (pKi 8.55) and rat (pKi 9.02) were similar suggesting a lack of species differences in 5-HT6 receptor for this given ligand. SB-271046 has greater than 200 fold selectivity over 69 other receptor, enzyme and binding sites, containing all other 5-HT receptor subtypes tested. SB-271046 did not alter basal levels of 5-HT, DA and NA in either brain region. In contrast, administration of SB-271046 (10mg.kg-1s.c.) produced an important and tetrodotoxin-dependent acceleration in extracellular levels of both glutamate and aspartate within the frontal cortex, reaching maximum values of 375.482.3 and 215.362.1% of preinjection values, respectively. [2]

References:
1.  Characterization of SB-271046: a potent, selective and orally active 5-HT(6) receptor antagonist. Br J Pharmacol. 2000 Aug;130(7):1606-12.
2.  In vivo effects of the 5-HT(6) antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5-HT, glutamate and aspartate. Br J Pharmacol. 2000 May;130(1):23-6.

5-HT6 receptor agonist and memory-enhancing properties of hypidone hydrochloride (YL-0919), a novel 5-HT1A receptor partial agonist and SSRI.[Pubmed:29805118]

Neuropharmacology. 2018 Aug;138:1-9.

Most current antidepressants are lacking a pro-cognition effect or even impair cognition as a side effect, and there are few effective psychopharmacological options that improve cognitive dysfunction in depression. Our previous studies revealed that hypidone hydrochloride (YL-0919), a novel 5-HT1A receptor partial agonist and SSRI, has antidepressant- and anxiolytic-like effects. Here, further studies found that YL-0919, but not vilazodone (a 5-HT1A receptor partial agonist and SSRI), exerted a significant memory-enhancing effect in the Morris water maze, object recognition test and step-down passive avoidance task. Because the 5-HT6 receptor has emerged as an interesting drug target to improve cognition, we investigated the target profile of YL-0919 using radioligand binding assays, [(35)S]-GTPgammaS binding and cAMP stimulation assays. YL-0919 was found to act as a highly effective, full agonist of 5-HT6 receptors. Finally, we observed that the memory-enhancing activities of YL-0919 were completely reversed after co-administration of SB271046 (a selective 5-HT6 receptor antagonist) at a dose that does not alter cognition. In summary, the findings of the current study suggest that YL-0919 has clear memory-enhancing effects, which might be at least partially mediated by 5-HT6 receptor activation.

Serotonin 5-HT6 receptors affect cognition in a mouse model of Alzheimer's disease by regulating cilia function.[Pubmed:28931427]

Alzheimers Res Ther. 2017 Sep 20;9(1):76.

BACKGROUND: Serotonin receptor 5-HT6 is involved in cognition and Alzheimer's disease (AD) development. However, the mechanism of 5-HT6 in AD pathology is not clear. METHODS: Since 5-HT6 is almost exclusively expressed in the primary cilia, using immunostaining we examined the number of cilia in the hippocampus of AD animal model APP/PS1 mice. By overexpressing and knocking down 5-HT6 in the primary cultured hippocampal neurons, we investigated the roles of 5-HT6 in alternating ciliary morphology. Furthermore, 5-HT6 antagonist was applied to confirm its roles in cognition using the Morris water maze test, Y maze, and fear conditioning. RESULTS: In the present study, we found that the primary cilia were elongated in the hippocampus of APP/PS1 mice compared with WT mice. 5-HT6 regulated cilia length, influenced cilia and axon initial segment (AIS) morphology, and affected localization of ARL13B and AnkG. We also found that, by changing cilia morphology, the AIS was elongated, branched, and more proximal to the cell body in both WT and APP/PS1 mouse neurons. Alterations of cilia also decreased the axonal length in WT and APP/PS1 neurons. Furthermore, in the water maze test, Y maze, and fear conditioning test, 5-HT6 antagonist SB271046 recovered the cognitive impairment of APP/PS1 mice. CONCLUSION: We suggest that 5-HT6 plays a critical role in AD development through regulating the morphology and function of neuronal primary cilia, which is possibly related to the AIS and axon alterations in AD development.

Effects of ST1936, a selective serotonin-6 agonist, on electrical activity of putative mesencephalic dopaminergic neurons in the rat brain.[Pubmed:25735994]

J Psychopharmacol. 2015 Jul;29(7):802-11.

The serotonin-6 (5-HT6) receptor is the most recently discovered serotonin receptor, and it represents an increasingly promising target for improving cognition in both normal and disease states. Recently, a new selective 5-HT6 receptor agonist, 2-(5 chloro-2-methyl-1H-indol-3-yl)-N,N-dimethylethanamine (ST1936), with nanomolar affinity for 5-HT6 receptors was described. We performed in-vivo electrophysiological studies to investigate the physiological role of 5-HT6 receptors in the control of the function of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Extracellular single-unit recordings were performed from putative dopamine-containing neurons in the SNc and VTA of anesthetised rats. In the SNc, acute systemic administration of ST1936 had no effects on basal firing activity of these dopamine neurons; however, in the VTA, ST1936 induced either dose-related increases (45% of cells) or decreases in basal activity of these dopaminergic neurons. Local application of ST1936 into the VTA caused excitation in all of the dopamine neurons, but had no effects on non-dopamine VTA neurons. Both effects of systemic and microiontophoretic ST1936 were completely reversed by the potent and selective 5-HT6 receptor antagonist 5-chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl-2- benzothiophene-sulfonamide (SB271046). Systemic application of another 5-HT6 agonist, 2-(1-{6-chloroimidazo[2,1-b] [1,3]thiazole-5-sulfonyl}-1H-indol-3-yl)ethan-1-amine (WAY-181187), induced dose-dependent inhibition of these VTA dopaminergic neurons. ST1936 and WAY-181187 appear to have different effects on these VTA dopaminergic neurons, potentially due to different mechanisms of action or to the complexity of 5-HT6 receptor functions. Our data demonstrate the need for further investigations into the use of 5-HT6 receptor agonists to control cognitive disfunction, such as in schizophrenia and depression.

Evidence for a role of a dopamine/5-HT6 receptor interaction in cocaine reinforcement.[Pubmed:22982249]

Neuropharmacology. 2013 Feb;65:58-64.

The putative 5-HT6 receptor agonist ST1936 has been shown to increase extracellular dopamine (DA) in the n.accumbens (NAc) shell and in the medial prefrontal cortex (PFCX). These observations suggest that 5-HT6 receptors modulate DA transmission in mesolimbic and mesocortical terminal DA areas. To investigate the behavioral counterpart of this interaction we studied in rats 1) the ability of ST1936 to maintain i.v. self-administration in fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement; 2) the effect of 5-HT6 receptor blockade on cocaine stimulated overflow of DA in dialysates from the PFCX and from the NAc shell and on cocaine i.v. self-administration. ST1936 was i.v. self-administered at unitary doses of 0.5-1 mg/kg on an FR1 and PR schedule of reinforcement, with breaking point of about 4. Pretreatment with the 5-HT6 antagonist SB271046 reduced by about 80% responding for ST1936. SB271046 also reduced cocaine-induced increase of dialysate DA in the NAc shell but not in the PFCX and impaired i.v. cocaine self-administration. These observations indicate that ST1936 behaves as a weak reinforcer and suggest that 5-HT6 receptors play a role in cocaine reinforcement via their facilitatory interaction with DA projections to the NAc shell. This novel 5-HT/DA interaction might provide the basis for a new pharmacotherapeutic strategy of cocaine addiction.

ST1936 stimulates cAMP, Ca2+, ERK1/2 and Fyn kinase through a full activation of cloned human 5-HT6 receptors.[Pubmed:21549693]

Eur J Pharmacol. 2011 Jul 1;661(1-3):8-14.

5-HT(6) receptor is one of the most recently cloned serotonin receptors, and it might play important roles in Alzheimer's disease, depression, and learning and memory disorders. Availability of only very few 5-HT(6) receptor agonists, however, does not allow examining their contribution in psychopharmacological processes. Therefore, a new 5-HT(6) receptor agonist, ST1936, was synthesized. ST1936 binds to human 5-HT(6) receptors with good affinity (K(i)=28.8 nM). ST1936 also exhibited some moderate binding affinity for 5HT(2B), 5HT(1A), 5HT(7) receptors and adrenergic alpha receptors. ST1936 behaved as a full 5-HT(6) agonist on cloned cells and was able to increase Ca(2+) concentration, phosphorylation of Fyn kinase, and regulate the activation of ERK1/2 that is a downstream target of Fyn kinase. These effects were completely antagonized by two 5-HT(6) receptor antagonists, SB271046 and SB258585. The other 5-HT(6) receptor agonist, WAY181187 also increased Fyn kinase activity. These results suggest that both ST1936 and WAY181187 mediate 5-HT(6) receptor-dependent signal pathways, such as cAMP, Fyn and ERK1/2 kinase, as specific agonists.

A microdialysis study of ST1936, a novel 5-HT6 receptor agonist.[Pubmed:21185318]

Neuropharmacology. 2011 Mar;60(4):602-8.

The function of 5-HT6 receptors, one of the last additions to the large family of 5-HT receptors, is largely unknown due to the limited knowledge of their transduction mechanisms, lack of full centrally acting agonists and inconsistencies in the pharmacological and neurochemical effects of the antagonists. Recently, a new full agonist, ST1936, with nanomolar affinity for 5-HT6 receptors, has become available. Here we report the effect of ST1936 (5-10-20 mg/kg/ip) on dialysate DA, NA and 5-HT in the medial prefrontal cortex (PFCX) and in the shell and core of the nucleus accumbens (NAc). Systemic administration of ST1936 dose-dependently increased dialysate DA and NA in the NAc shell and PFCX and to a lesser extent in the NAc core; these effects were prevented by systemic administration of the two 5-HT6 receptor antagonists, SB271046 (10-20 mg/kg/ip) and SB399885 (5 mg/kg/ip). These properties of ST1936 suggest that 5-HT6 receptors control the activity of DA and NA neurons projecting to the NAc and to the PFCX.

Functional interaction between 5-HT(6) receptors and hypothalamic-pituitary-adrenal axis: cognitive implications.[Pubmed:18206183]

Neuropharmacology. 2008 Mar;54(4):708-14.

The serotonin 5-HT(6) receptor has become a promising target for the treatment of neuropsychological diseases, such as affective disorders. Increasing evidence implicates stress and its effector system, the hypothalamic-pituitary-adrenal (HPA) axis, in the neurobiology of depression. In addition, there are important memory disturbances in stress-related psychiatric disorders that have been associated to an impairment of the HPA axis reactivity. The aim of the present work is to study the functional interactions between 5-HT(6) receptors and HPA axis. In a situation of increased HPA axis responsiveness (maternal separation, MS) no differences were found in the expression of 5-HT(6) gene in the hippocampus or frontal cortex, although serotonin levels were higher in the frontal cortex of MS rats. 5-HT(6) receptor mRNA expression increased significantly in the hippocampus in a situation of decreased glucocorticoid levels, such as adrenalectomy. Cognitive deficits associated to HPA dysfunction, such those found in the MS model, were fully reversed by administration of SB271046, a selective 5-HT(6) receptor antagonist. A chronic treatment with SB271046 did not modify CRF mRNA levels in the hypothalamus, but there was a higher glucocorticoid receptor density in the hippocampus compared to control. In contrast, in the frontal cortex, treatment with SB271046 induced a significant decrease in glucocorticoid receptor density. These data suggest that expression of 5-HT(6) receptors might be differentially regulated depending on levels of circulating adrenal corticoids. These results are discussed in terms of therapeutical approaches to the treatment of behavioral (depressive-like) and cognitive disturbances associated to an altered response to stress.

Biochemical and behavioral evidence for antidepressant-like effects of 5-HT6 receptor stimulation.[Pubmed:17428998]

J Neurosci. 2007 Apr 11;27(15):4201-9.

The primary action of several antidepressant treatments used in the clinic raises extracellular concentrations of serotonin (5-HT), which subsequently act on multiple 5-HT receptors. The present study examined whether 5-HT6 receptors might be involved in the antidepressant-like effects mediated by enhanced neurotransmission at 5-HT synapses. A selective 5-HT6 receptor antagonist, SB271046, was evaluated for its ability to counteract fluoxetine-induced biochemical and behavioral responses in mice. In addition, biochemical and behavioral effects of the 5-HT6 receptor agonist, 2-ethyl-5-methoxy-N,N-dimethyltryptamine (EMDT), were assessed in mice to ascertain whether enhancement of 5-HT6 receptor-mediated neurotransmission engenders antidepressant-like effects. SB271046 significantly counteracted the stimulatory actions of fluoxetine on cortical c-fos mRNA, phospho-Ser845-GluR1, and in the tail suspension antidepressant assay, whereas it had no effect on these parameters by itself. EMDT increased the phosphorylation states of Thr34-DARPP-32 and Ser845-GluR1, both in brain slices and in the intact brain, which were effects also seen with the antidepressant fluoxetine; as with fluoxetine, these effects were demonstrated to be independent of D1 receptor stimulation. Systemic administration of EMDT increased c-fos mRNA expression in the striatum and cerebral cortex and reduced immobility in the tail suspension test. The antidepressant-like effects of EMDT in the tail suspension test were prevented by SB271046. Our results indicate that 5-HT6 receptor stimulation may be a mechanism initiating some of the biochemical and behavioral outcomes of 5-HT reuptake inhibitors, such as fluoxetine. These findings also indicate that selective 5-HT6 receptor agonists may represent a novel antidepressant drug class.