Selective 5-HT3 Receptor Antagonist Research Articles

Effects of psilocin and psilocybin on human 5-HT4 serotonin receptors in atrial preparations of transgenic mice and humans

Several fungi belonging to the genus Psilocybe, also called “magic mushrooms”, contain the hallucinogenic drugs psilocybin and psilocin. They are chemically related to serotonin (5-HT). In addition to being abused as drugs, they are now also being discussed or used as a treatment option for depression. Here, we hypothesized that psilocybin and psilocin may act also on cardiac serotonin receptors and studied them in vitro in atrial preparations of our transgenic mouse model with cardiac myocytes-specific overexpression of the human 5-HT4 receptor (5-HT4-TG) as well as in human atrial preparations. Both psilocybin and psilocin enhanced the force of contraction in isolated left atrial preparations from 5-HT4-TG, increased the beating rate in isolated spontaneously beating right atrial preparations from 5-HT4-TG and augmented the force of contraction in the human atrial preparations. The inotropic and chronotropic effects of psilocybin and psilocin at 10 µM were smaller than that of 1 µM 5-HT on the left and right atria from 5-HT4-TG, respectively. Psilocybin and psilocin were inactive in WT. In the human atrial preparations, inhibition of the phosphodiesterase III by cilostamide was necessary to unmask the positive inotropic effects of psilocybin or psilocin. The effects of 10 µM psilocybin and psilocin were abrogated by 10 µM tropisetron or by 1 µM GR125487, a more selective 5-HT4 receptor antagonist. In summary, we demonstrated that psilocin and psilocybin act as agonists on cardiac 5-HT4 receptors.

Novel 5-HT7 receptor antagonists modulate intestinal immune responses and reduce severity of colitis.

Inflammatory bowel disease (IBD) encompasses several debilitating chronic gastrointestinal (GI) inflammatory disorders, including Crohn's disease and ulcerative colitis. In both conditions, mucosal inflammation is a key clinical presentation associated with altered serotonin (5-hydroxytryptamine or 5-HT) signaling. This altered 5-HT signaling is also found across various animal models of colitis. Of the 14 known receptor subtypes, 5-HT receptor type 7 (5-HT7) is one of the most recently discovered. We previously reported that blocking 5-HT signaling with either a selective 5-HT7 receptor antagonist (SB-269970) or genetic ablation alleviated intestinal inflammation in murine experimental models of colitis. Here, we developed novel antagonists, namely, MC-170073 and MC-230078, which target 5-HT7 receptors with high selectivity. We also investigated the in vivo efficacy of these antagonists in experimental colitis by using dextran sulfate sodium (DSS) and the transfer of CD4+CD45RBhigh T cells to induce intestinal inflammation. Inhibition of 5-HT7 receptor signaling with the antagonists, MC-170073 and MC-230078, ameliorated intestinal inflammation in both acute and chronic colitis models, which was accompanied by lower histopathological damage and diminished levels of proinflammatory cytokines compared with vehicle-treated controls. Together, the data reveal that the pharmacological inhibition of 5-HT7 receptors by these selective antagonists ameliorates the severity of colitis across various experimental models and may, in the future, serve as a potential treatment option for patients with IBD. In addition, these findings support that 5-HT7 is a viable therapeutic target for IBD.NEW & NOTEWORTHY This study demonstrates that the novel highly selective 5-HT7 receptor antagonists, MC-170073 and MC-230078, significantly alleviated the severity of colitis across models of experimental colitis. These findings suggest that inhibition of 5-HT7 receptor signaling by these new antagonists may serve as an alternative mode of treatment to diminish symptomology in those with inflammatory bowel disease.

The 5-HT7 receptor antagonist SB 269970 ameliorates maternal fluoxetine exposure-induced impairment of synaptic plasticity in the prefrontal cortex of the offspring female mice

The use of a selective serotonin reuptake inhibitor fluoxetine in depression during pregnancy and the postpartum period might increase the risk of affective disorders and cognitive symptoms in progeny. In animal models, maternal exposure to fluoxetine throughout gestation and lactation negatively affects the behavior of the offspring. Little is known about the effects of maternal fluoxetine on synaptic transmission and plasticity in the offspring cerebral cortex. During pregnancy and lactation C57BL/6J mouse dams received fluoxetine (7.5 mg/kg/day) with drinking water. Female offspring mice received intraperitoneal injections of the selective 5-HT7 receptor antagonist SB 269970 (2.5 mg/kg) for 7 days. Whole-cell and field potential electrophysiological recordings were performed in the medial prefrontal cortex (mPFC) ex vivo brain slices. Perinatal exposure to fluoxetine resulted in decreased field potentials and impaired long-term potentiation (LTP) in layer II/III of the mPFC of female young adult offspring. Neither the intrinsic excitability nor spontaneous excitatory postsynaptic currents were altered in layer II/III mPFC pyramidal neurons. In mPFC slices obtained from fluoxetine-treated mice that were administered SB 269970 both field potentials and LTP magnitude were restored and did not differ from controls. Treatment of fluoxetine-exposed mice with a selective 5-HT7 receptor antagonist, SB 269970, normalizes synaptic transmission and restores the potential for plasticity in the mPFC of mice exposed in utero and postnatally to fluoxetine.

Nausea and vomiting induced by pharmacotherapy: have all issues of maintenance therapy been resolved?

Many patients with various localizations of malignant neoplasms require therapy aimed at preventing or reducing the manifestations of nausea and vomiting induced by anticancer pharmacotherapy. New drugs to prevent the development of complications of chemotherapy are critical to improve the quality of life of patients and their adherence to therapy. Palonosetron, a new generation 5-HT3 receptor antagonist, has a long half-life (up to 40 hours) and a 30-fold higher affinity for 5-HT3 receptors compared to previous generations of 5-HT3 receptor antagonists. Clinical studies have shown the ability of palonosetron in combination with dexamethasone and, if indicated, neurokinin antagonists to effectively prevent the development of nausea and vomiting during single- and multi-day cycles of chemotherapy for both solid tumors and hematological diseases, including high-dose chemotherapy, in preparation for transplantation of auto- and allogeneic stem cells. The innovative oral drug Akynzeo is currently available for use in clinical practice, which includes 2 highly selective NK1 and 5-HT3 receptor antagonists in fixed doses. The drug prevents induced nausea and vomiting during moderate and highly emetogenic chemotherapy in more than 90 % of cases, both in the acute and delayed phases.

5-HT7 receptors mediate dilation of rat cremaster muscle arterioles in vivo.

Serotonin (5-HT) infusion in vivo causes hypotension and a fall in total peripheral resistance. However, the vascular segment and the receptors that mediate this response remain in question. We hypothesized that 5-HT7 receptors mediate arteriolar dilation to 5-HT in skeletal muscle microcirculation. Cremaster muscles of isoflurane-anesthetized male Sprague-Dawley rats were prepared for in vivo microscopy of third- and fourth-order arterioles and superfused with physiological salt solution at 34°C. Quantitative real-time PCR (RT-PCR) was applied to pooled samples of first- to third-order cremaster arterioles (2-4 rats/sample) to evaluate 5-HT7 receptor expression. Topical 5-HT (1-10 nmols) or the 5-HT1/7 receptor agonist, 5-carboxamidotryptamine (10-30 nM), dilated third- and fourth-order arterioles, responses that were abolished by 1 μM SB269970, a selective 5-HT7 receptor antagonist. In contrast, dilation induced by the muscarinic agonist, methacholine (100 nmols) was not inhibited by SB269970. Serotonin (10 nmols) failed to dilate cremaster arterioles in 5-HT7 receptor knockout rats whereas arterioles in wild-type litter mates dilated to 1 nmol 5-HT, a response blocked by 1 μM SB269970. Quantitative RT-PCR revealed that cremaster arterioles expressed mRNA for 5-HT7 receptors. 5-HT7 receptors mediate dilation of small arterioles in skeletal muscle and likely contribute to 5-HT-induced hypotension, in vivo.

Descending serotonergic modulation from rostral ventromedial medulla to spinal trigeminal nucleus is involved in experimental occlusal interference-induced chronic orofacial hyperalgesia

BackgroundDental treatment associated with unadaptable occlusal alteration can cause chronic primary myofascial orofacial pain. The serotonin (5-HT) pathway from the rostral ventromedial medulla (RVM) exerts descending modulation on nociceptive transmission in the spinal trigeminal nucleus (Sp5) and facilitates chronic pain. The aim of this study was to investigate whether descending 5-HT modulation from the RVM to the Sp5 is involved in the maintenance of primary myofascial orofacial hyperalgesia after persistent experimental occlusal interference (PEOI) or after delayed removal of experimental occlusal interference (REOI).MethodsExpressions of 5-HT3A and 5-HT3B receptor subtypes in the Sp5 were assessed by immunofluorescence staining and Western blotting. The release and metabolism of 5-HT in the Sp5 were measured by high-performance liquid chromatography. Changes in the pain behavior of these rats were examined after specific pharmacologic antagonism of the 5-HT3 receptor, chemogenetic manipulation of the RVM 5-HT neurons, or selective down-regulation of 5-HT synthesis in the RVM.ResultsUpregulation of the 5-HT3B receptor subtype in the Sp5 was found in REOI and PEOI rats. The concentration of 5-HT in Sp5 increased significantly only in REOI rats. Intrathecal administration of Y-25130 (a selective 5-HT3 receptor antagonist) dose-dependently reversed the hyperalgesia in REOI rats but only transiently reversed the hyperalgesia in PEOI rats. Chemogenetic inhibition of the RVM 5-HT neurons reversed the hyperalgesia in REOI rats; selective down-regulation of 5-HT in advance also prevented the development of hyperalgesia in REOI rats; the above two manipulations did not affect the hyperalgesia in PEOI rats. However, chemogenetic activation of the RVM 5-HT neurons exacerbated the hyperalgesia both in REOI and PEOI rats.ConclusionsThese results provide several lines of evidence that the descending pathway from 5-HT neurons in the RVM to 5-HT3 receptors in the Sp5, plays an important role in facilitating the maintained orofacial hyperalgesia after delayed EOI removal, but has a limited role in that after persistent EOI.Graphical

Progress in Investigational Agents Targeting Serotonin-6 Receptors for the Treatment of Brain Disorders.

Serotonin (5-HT) plays an important role in the regulation of several basic functions of the central and peripheral nervous system. Among the 5-HT receptors, serotonin-6 (5-HT6) receptor has been an area of substantial research. 5-HT6 receptor is a G-protein-coupled receptor mediating its effects through diverse signaling pathways. Exceptional features of the receptors fueling drug discovery efforts include unique localization and specific distribution in the brain regions having a role in learning, memory, mood, and behavior, and the affinity of several clinically used psychotropic agents. Although non-clinical data suggest that both agonist and antagonist may have similar behavioral effects, most of the agents that entered clinical evaluation were antagonists. Schizophrenia was the initial target; more recently, cognitive deficits associated with Alzheimer's disease (AD) or other neurological disorders has been the target for clinically evaluated 5-HT6 receptor antagonists. Several 5-HT6 receptor antagonists (idalopirdine, intepirdine and latrepirdine) showed efficacy in alleviating cognitive deficits associated with AD in the proof-of-concept clinical studies; however, the outcomes of the subsequent phase 3 studies were largely disappointing. The observations from both non-clinical and clinical studies suggest that 5-HT6 receptor antagonists may have a role in the management of neuropsychiatric symptoms in dementia. Masupirdine, a selective 5-HT6 receptor antagonist, reduced agitation/aggression-like behaviors in animal models, and a post hoc analysis of a phase 2 trial suggested potential beneficial effects on agitation/aggression and psychosis in AD. This agent will be assessed in additional trials, and the outcome of the trials will inform the use of 5-HT6 receptor antagonists in the treatment of agitation in dementia of the Alzheimer's type.

The use of granisetron on bupivacaine induced sciatic nerve block in rats

Purpose The effects of the 5-hydroxytryptamine (5-HT3) receptor antagonists on regional anaesthesia are complex and unclear. The present study was designed to test the hypothesis that granisetron, a selective 5-HT3 receptor antagonist, would decrease the duration of motor block, sensory block, and proprioception in a dose-dependent fashion in a rat model of bupivacaine-induced sciatic nerve blockade. Materials and methods Thirty-eight male Wistar Albino rats that received unilateral sciatic nerve blocks were randomly divided into five experimental groups. Group B received a perineural of 0.3 ml of bupivacaine alone; Group BG800 received perineural 0.3 ml of bupivacaine and 800 µg of granisetron 10 min later; Group BG1200 received perineural 0.3 ml of bupivacaine and 1200 µg of granisetron 10 min later; Group BG1200IP received a perineural 0.3 ml of bupivacaine and an intraperitoneal injection of 1200 µg of granisetron 10 min later; and Group S was sham operated. A blinded investigator assessed motor, sensory and proprioception function every 10 min until the return of normal function. Results The medians for recovery times in Group B, Group BG800, Group BG1200, and Group BG1200IP were 105, 64, 85, and 120 min for motor function, respectively; 80, 64, 84, and 104 min for sensory function; 80, 63, 85, and 108 min were calculated for the proprioception function. The time to the return of normal motor, sensory, and proprioception function was not statistically significantly different between the groups (p > 0.05). Motor block did not develop in any of the rats in Group S. Conclusions Local and systemic application of granisetron was not significantly decrease the duration of bupivacaine induced motor, sensory, and proprioception block of sciatic nerve in rat.

Ondansetron: A selective 5HT3 receptor antagonist and it advances in drug delivery system

Ondansetron: A selective 5HT3 receptor antagonist and it advances in drug delivery system

Ondansetron: A selective 5HT3 receptor antagonist and it advances in drug delivery system

Ondansetron is a serotonin (5HT3) receptor antagonist used for the prevention and treatment of postoperative nausea and vomiting. It is available in many dosage forms in the market. Various analytical methods used for the determination of Ondansetron have been studied in this review article such as UV spectroscopy, mass spectroscopy, high-performance liquid chromatography, high-performance thin layer chromatography, a new electrospray ionization mass spectrometry etc. Ondansetron in human plasma can be estimated using this method. With time many advances have been made in the formulation aspects of Ondansetron, such as now a days it is available in floating drug delivery, transdermal as well as gastroretentive and orodispersible drug delivery system. New novel technologies are also mentioned in this review article related to 3D printing, nanofibers etc

Intranasal ondansetron microemulsion counteracting the adverse effects of cisplatin: animal study

BackgroundCisplatin is considered one of the most effective and commonly used chemotherapeutic drugs, but despite its high therapeutic effectiveness, most patients treated with cisplatin suffer from nausea and vomiting, neurotoxic side effects, and cerebral psychiatric disorders such as depression. Therefore, the aim of the current work was to explore whether a selective 5-HT3 receptor antagonist (Ondansetron) administered via the oral route or intranasally in microemulsion form would alleviate cisplatin’s adverse effects.MethodsThe selected ondansetron microemulsion was characterized in vitro for particle size, polydispersity, zeta potential, morphology, and nasal permeation, and in vivo in terms of anti-emetic and antidepressant activity, with the assessment of biochemical markers in brain homogenates.ResultsResults revealed that both orally administered ondansetron and intranasally administered microemulsion were able to counteract the pica effect by increasing food consumption, water intake, and decreasing kaolin intake. They were also able to increase BDNF, normalize IL-6, increase serotonin, and normalize NOx, MDA, GSSH/GSH as well as 8OHdG levels in rats’ brain homogenates. The intranasal ondansetron microemulsion displayed superiority compared to oral conventional ondansetron in terms of increasing food intake, reduction of stomach content, and normalization of serotonin turnover.ConclusionOndansetron microemulsion can be administered by an alternative route of administration (intranasal) rather than oral, for patients on cisplatin chemotherapy.Graphical

Effect of Concurrent Use of Memantine on the Efficacy of Masupirdine (SUVN-502): A Post Hoc Analysis of a Phase2 Randomized Placebo-Controlled Study.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive deterioration in cognition, memory and activities of daily living. Selective blockade of serotonin-6 (5-HT6) receptors, which are exclusively localized to the central nervous system, is reported to play an important role in learning and memory. Masupirdine is a potent and selective 5-HT6 receptor antagonist with pro-cognitive properties in animal models of cognition. The efficacy and safety of masupirdine were evaluated in patients with moderate AD concurrently treated with donepezil and memantine. A total of 564 patients were randomized in a 1:1:1 ratio. The study consisted of a 26-week double-blind treatment period. The primary efficacy outcome was the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog 11). Changes from baseline were analyzed using a mixed effects model for repeated measures (MMRM). In exploratory post hoc analyses, patients were subdivided based on the use of memantine dosage forms and memantine plasma concentrations, to evaluate the impact of memantine on the efficacy of masupirdine. In an exploratory post hoc analysis, less worsening in cognition (ADAS-Cog 11 scores) was observed with masupirdine treatment as compared with placebo in patients whose trough memantine plasma concentrations were ≤ 100ng/mL. Although prespecified study endpoints of the phase2 study were not met, these exploratory post hoc subgroup observations are hypothesis-generating and suggest that the efficacy of masupirdine was adversely affected by concurrent therapy with memantine. Further assessment of masupirdine to determine its potential role as a treatment option for cognitive deficits associated with AD is warranted. The study was registered at ClinicalTrials.gov (NCT02580305).

COMPARISON OF TWO DIFFERENT DOSAGES OF COMBINATION OF INTRAVENOUS GRANISETRON WITH INTRAVENOUS DEXAMETHASONE AS A PROPHYLAXIS FOR NAUSEA AND VOMITING IN CAESAREAN SECTION WITH SUBARACHNOID BLOCK

Granisetron can be used to treat and prevent nausea and vomiting in patients receiving chemotherapy or radiotherapy, as well as during or after surgery. To compare the effects of two doses of intravenous granisetron on nausea and vomiting in Caesarean section with subarachnoid block. This study was a randomized double-blind clinical trial. Subjects were randomized into two groups: Granisetron 10 mcg/kg (GD10) and granisetron 25 mcg/kg (GD25). Dexamethasone 0.1 mg/kg was also administered to all subjects. A total of 21 subjects were included for each group. Data was analyzed using Mann Whitney U test. The results When comparing the incidence of nausea and vomiting in the GD10 and GD25 groups, there was a significant difference in the incidence of nausea (p = 0.001). In the GD10 group, there were nine participants who experienced nausea, whereas the GD25 group had none. Neither of the groups experienced vomiting, hence no additional therapy given to both groups. Granisetron is a selective 5-HT3 receptor antagonist and an effective antiemetic during and after neuraxial anesthesia for Caesarean section. The combination of granisetron and dexamethasone has been reported to be more potent than granisetron alone. Administration of granisetron 25 mcg/kg had a positive impact on patients, with no incidence of nausea and vomiting compared to administration of granisetron 10 mcg/kg.

5‐HT7 Receptors Mediate Dilation of Rat Cremaster Muscle Arterioles in vivo

Serotonin (5‐HT) infusion in vivo causes hypotension and a fall in total peripheral resistance (TPR) that is mediated by 5‐HT7 receptors. 5‐HT dilates small arterioles in skeletal muscle, a microcirculation that importantly contributes to TPR. However, the receptors that mediate this dilation have not been established. Therefore, we tested the hypothesis that 5‐HT7 receptors mediate the arteriolar dilation in the skeletal muscle microcirculation. Cremaster muscles of isoflurane‐anesthetized male Sprague‐Dawley rats were prepared for digital in vivo microscopy and superfused with physiological salt solution (PSS) at 34 °C. Bolus (1‐10 nmols) application of 5‐HT into the superfusate caused substantial dilation of 3rd to 5th order arterioles from 10 ± 1 to 27 ± 1 μm (n = 10 arterioles from 4 rats, p <0.0001) that recovered within 2‐3 min. Dilation to bolus application of 5‐HT was inhibited by superfusion with 1 μM SB269970, a selective 5‐HT7 receptor antagonist (diameter in SB = 9 ± 1 μm; diameter in SB + 5‐HT = 10 ± 1 μm; n = 10 arterioles from 4 rats; p = 0.8763). Similarly, steady‐state superfusion with 10‐30 nM of the 5‐HT1/7 receptor agonist 5‐carboxamidotryptamine (5‐CT) dilated 3rd‐5th‐order arterioles from 16 ± 3 to 37 ± 5 μm (n = 7 arterioles from 3 rats, p = 0.0004). This dilation was reversed (diameter in 1 μM SB269970 = 13 ± 2 μm, n = 7, p = 0.1479 vs. baseline) or blocked (diameter in 1 μM SB269970 + 10‐30 nM 5‐CT = 10 ± 2 μm, n = 7, p = 0.0005 vs. 5‐CT alone) by 1 μM SB269970. Dilation of arterioles to the muscarinic agonist, methacholine (MCH) was not inhibited by SB269970 verifying the specificity of the antagonist; arterioles dilated from 13 ± 2 μm to 25 ± 2 μm to 100 nmols MCH and dilated from 9 ± 2 μm to 32 ± 2 μm in response to MCH in the presence of 1 μM SB269970; n = 10 arterioles from 4 rats; p = 0.7232 vs. dilation in the absence of SB269970. Consistent with these data, pooled samples (4‐5 rats) of 1st and 2nd – order cremaster arterioles expressed message for 5‐HT7 receptors by quantitative real‐time PCR (CT = 36.4 ± 0.74, n = 3 pooled samples, p = 0.039 vs CT = 40). These data support our hypothesis that 5‐HT7 receptors mediate dilation of small arterioles in skeletal muscle and likely contribute to the observed hypotension when these receptors are engaged in vivo.

Effect of ramosetron, a 5-HT3 receptor antagonist on the severity of seizures and memory impairment in electrical amygdala kindled rats

The entorhinal cortex (EC) plays a pivotal role in epileptogenesis and seizures. EC expresses high density of serotonergic receptors, especially 5-HT3 receptors. Cognitive impairment is common among people with epilepsy. The present study investigated the role of 5-HT3 receptor on the severity of seizures and learning and memory impairment by electrical kindling of amygdala in rats. The amygdala kindling was conducted in a chronic kindling manner in male Wistar rats. In fully kindled animals, ramosetron (as a potent and selective 5-HT3 receptor antagonist) was microinjected unilaterally (ad doses of 1, 10 or 100 µg/0.5 µl) into the EC 5 min before the novel object recognition (NOR) and Y-maze tests or kindling stimulations. Applying ramosetron at the concentration of 100 μg/0.5 µl (but not at 1 and 10 µg/0.5 µl) reduced afterdischarge (AD) duration and increased stage 4 latency in the kindled rats. Moreover, the obtained data from the NOR test showed that treatment by ramosetron (10 and 100 µg/0.5 µl) increased the discrimination index in the fully kindled animals. Microinjection of ramosetron (10 and 100 µg/0.5 µl) in fully kindled animals reversed the kindling induced changes in the percentage of spontaneous alternation in Y-maze task. The findings demonstrated an anticonvulsant role for a selective 5-HT3 receptor antagonist microinjected into the EC, therefore, suggesting an excitatory role for the EC 5-HT3 receptors in the amygdala kindling model of epilepsy. This anticonvulsive effect was accompanied with a restoring effect on cognitive behavior in NOR and Y-maze tests.

The reversing effect of ondansetron on bupivacaine-induced sciatic nerve block.

This experimental study was designed to test the hypothesis that ondansetron, a selective 5-HT3 receptor antagonist, would decrease the duration of motor, sensory, and proprioception blockade in a dose-dependent fashion in a bupivacaine-induced sciatic nerve blockade. Forty-nine male Wistar Albino rats who underwent unilateral sciatic nerve block were divided into seven groups with an equal number in each group. Group B: only perineural block (PB), Group BO200: PB and perineural 200 μg ondansetron, Group BO400: PB and perineural 400 μg ondansetron, Group BO800: PB and perineural 800 μg ondansetron, Group BO800IP: PB and intraperitoneal 800 μg ondansetron, Group O800: only perineural 800 μg ondansetron, Group S: sham-operated. The rats' motor, sensory, and proprioception functions were evaluated by a blinded investigator every 10 min until they returned to normal function. The recovery times of the motor, sensory, and proprioception functions were recorded and compared. All sciatic nerves were removed and examined by electron microscopy for neurotoxic signs. In which sciatic nerve block was formed with bupivacaine, the duration of the motor, sensory, and proprioception functions blockade was decreased, and the duration to return to normal functions was significantly shortened at Group BO800 (p < 0.05). According to electron microscopy results, perineural 200 μg, 400 μg, and 800 μg ondansetron were not neurotoxic. This is the first study showing that perineural ondansetron administration (800 μg dose) reverses the effect of the local anesthetics and shortens the duration of the motor, sensory, and proprioception functions blockade.

5-HT7 Receptor Is Involved in Electroacupuncture Inhibition of Chronic Pain in the Spinal Cord.

Knee osteoarthritis (KOA) is a common and disabling condition characterized by attacks of pain around the joints, and it is a typical disease that develops chronic pain. Previous studies have proved that 5-HT1, 5-HT2, and 5-HT3 receptors in the spinal cord are involved in electroacupuncture (EA) analgesia. The 5-HT7 receptor plays antinociceptive role in the spinal cord. However, it is unclear whether the 5-HT7 receptor is involved in EA analgesia. The 5-HT7 receptor is a stimulatory G-protein (Gs)-coupled receptor that activates adenylyl cyclase (AC) to stimulate cyclic adenosine monophosphate (cAMP) formation, which in turn activates protein kinase A (PKA). In the present study, we found that EA significantly increased the tactile threshold and the expression of the 5-HT7 receptor in the dorsal spinal cord. Intrathecal injection of 5-HT7 receptor agonist AS-19 mimicked the analgesic effect of EA, while a selective 5-HT7 receptor antagonist reversed this effect. Moreover, intrathecal injection of AC and PKA antagonists prior to EA intervention prevented its anti-allodynic effect. In addition, GABAA receptor antagonist bicuculline administered (intrathecal, i.t.) prior to EA intervention blocked the EA effect on pain hypersensitivity. Our data suggest that the spinal 5-HT7 receptor activates GABAergic neurons through the Gs–cAMP–PKA pathway and participates in EA-mediated inhibition of chronic pain in a mouse model of KOA.

N-(2,7-dimethyl-2-alkyl-2H-chromen-6-yl)sulfonamide derivatives as selective serotonin 5-HT6 receptor antagonists: Design, synthesis, and biological evaluation

Serotonin 5-HT6 receptor, which is predominantly expressed in the central nervous system, is a valuable therapeutic target. Serotonin 5-HT6 receptor antagonists have potential for the treatment of various diseases that include psychotic disorders, dementia, depression, and obesity. In this study, we designed and synthesized the N-(2,7-dimethyl-2-alkyl-2H-chromen-6-yl)sulfonamide-based library as a potential serotonin 5-HT6 receptor antagonist. The library was subjected to a series of binding affinity tests to identify the lead compound, and check the selectivity of test compounds towards the 5-HT6 receptor. Accordingly, compound 6m was identified as the most active compound, with IC50 = 87 nM. The binding affinity of 95.3% of 6m (10 μM) with the 5-HT6 receptor among other serotonin 5-HT1a, 5-HT2a, 5-HT2c, and 5-HT7, and dopamine receptors D1, D2, D3, and D4, demonstrated the high selectivity of 6m towards the 5-HT6 receptor.

Safety, Tolerability and Pharmacokinetics of the Serotonin 5-HT6 Receptor Antagonist, HEC30654, in Healthy Chinese Subjects.

Background and Objective: HEC30654 is a selective 5-HT6 receptor antagonist that was safe and well-tolerated in preclinical models of Alzheimer’s disease. The objective of this double-blind, randomized, placebo-controlled clinical trial was to evaluate the safety, tolerability, and pharmacokinetic profile of HEC30654 after single ascending doses in healthy Chinese subjects.Methods: Healthy volunteers received a single oral dose of HEC30654 (5, 10, 15, 30, 60 mg). Safety and tolerability assessments included adverse events, vital signs, and findings on electrocardiograms, electroencephalograms, physical examination, and clinical laboratory tests. Pharmacokinetic analysis of HEC30654 and its major metabolite HEC93263 were conducted in blood, urine, and fecal samples.Results: Single doses of HEC30654 up to 30 mg were generally safe and well tolerated, but dose escalation was terminated early as the 60 mg HEC30654 treatment group met the pre-defined stopping rules specified in the protocol. Median tmax of HEC30654 was 6 h (range, 4–12 h), t1/2 of 10–60 mg HEC30654 ranged from 52.1 to 63.8 h. Exposure to HEC30654 across the dose range explored in this study increased more than in proportion to dose. Metabolism of HEC30654 to HEC93263 was slow (<10%), and HEC30654 was mainly eliminated unchanged through feces.Conclusion: Single doses of HEC30654 up to 30 mg were generally safe and well tolerated. Based on preclinical efficacy in various models of cognition, HEC30654 may represent a therapeutic option for symptomatic treatment of cognitive disorders.

Identification of CVN058, a Novel Brain Penetrant, Selective 5-HT3 Receptor Antagonist That Shows Efficacy in Pre-Clinical Cognition Models

Maintaining excitatory/inhibitory balance is essential for the synchronised signalling required for cognitive function and is impaired in schizophrenia. Evidence from clinical and pre-clinical research have implicated GABAergic interneuronsin this synchronised signalling. Therefore, modulating interneuron activity has therapeutic potential for improving cognitive function. The 5-HT3 receptor (5-HTR3) is expressed on a subset of interneurons in the cortex and existing antagonists of this receptor have been shown to modulate cortical function, but have poor CNS drug-like characteristics and unsuitable pharmacokinetic or off-target activity, precluding use for schizophrenia. Here we describe the development of CVN058, a 5-HTR3 antagonist with good CNS properties and potential for the treatment of cognitive impairment associated with schizophrenia (CIAS).