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Clinical Drug Investigation May 2018SUVN-502, a selective 5-HT6 receptor antagonist, was found to be active in preclinical models of cognitive deterioration suggesting a potential role in the treatment of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVE
SUVN-502, a selective 5-HT6 receptor antagonist, was found to be active in preclinical models of cognitive deterioration suggesting a potential role in the treatment of dementia related to Alzheimer's disease. The objective of this study was to characterize the safety, tolerability and pharmacokinetics of SUVN-502 in healthy young adults and elderly subjects following single and multiple oral doses.
METHODS
Single doses (5, 15, 50, 100 and 200 mg SUVN-502) and multiple doses (50, 100 and 130 mg SUVN-502 once daily for 7 days) were evaluated in healthy young adults and multiple doses (50 and 100 mg SUVN-502 once daily for 14 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food, gender and age on SUVN-502 pharmacokinetics (100 mg single dose) was evaluated using an open-label, two-period, randomized, fed and fasted in a crossover design. SUVN-502 and M1 (major metabolite of SUVN-502) were monitored using validated analytical methods.
RESULTS
SUVN-502 is safe and well tolerated up to the highest tested single dose of 200 mg in healthy young adults and multiple doses up to 130 mg for 7 days and 100 mg for 14 days in healthy young adults and elderly subjects, respectively. Exposures of SUVN-502 and M1 were more than dose-proportional over the evaluated dose range. Food and gender did not have a clinically meaningful effect on SUVN-502 exposure. The mean SUVN-502 total (AUC, and AUC) and peak exposures (C) were 2.9- and 2.2-fold higher, respectively, in elderly subjects compared to young subjects. Steady-state was achieved for SUVN-502 and M1 within 7 days after once-daily dosing of SUVN-502.
CONCLUSIONS
SUVN-502 exhibited an acceptable safety, tolerability and pharmacokinetic profile in healthy young adults and elderly subjects. Based on the above results, 50 and 100 mg once-daily doses of SUVN-502 were advanced to Phase 2 evaluation in patients with moderate AD.
Topics: Administration, Oral; Adult; Aged; Alzheimer Disease; Area Under Curve; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indoles; Male; Piperazines; Receptors, Serotonin; Serotonin Antagonists; Young Adult
PubMed: 29380267
DOI: 10.1007/s40261-018-0618-4 -
European Journal of Medicinal Chemistry Mar 2021We have previously reported that dual 5-HT and 5-HT receptor ligands might find utility as treatment options for various CNS related conditions including cognitive and...
We have previously reported that dual 5-HT and 5-HT receptor ligands might find utility as treatment options for various CNS related conditions including cognitive and anxiolytic impairments. We have also more recently reported that SYA16263 has antipsychotic-like properties with an absence of catalepsy in animal models ascribed to its ability to recruit β-arrestin to the D receptor. However, SYA16263 also binds with very high affinity to 5-HTR (Ki = 1.1 nM) and a moderate affinity at 5-HTR (Ki = 90 nM). Thus, it was of interest to exploit its pharmacophore elements in designing new dual receptor ligands. Using SYA16263 as the lead molecule, we have conducted a limited structure-affinity relationship (SAFIR) study by modifying various structural elements in the arylalkyl moiety, resulting in the identification of a new dual 5-HTR and 5-HTR ligand, 6-chloro-2-methyl-2-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-2,3-dihydro-1H-inden-1-one (21), which unlike SYA16263, has a sub-nanomolar (5-HTR, Ki = 0.74 nM) and a low nanomolar (5-HTR, Ki = 8.4 nM) affinity for these receptors. Interestingly, 21 is a full agonist at 5-HTR and antagonist at the 5-HTR, functional characteristics which point to its potential as an antidepressant agent.
Topics: Dose-Response Relationship, Drug; Humans; Ligands; Molecular Structure; Piperazines; Pyridines; Receptor, Serotonin, 5-HT1A; Receptors, Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin Antagonists; Structure-Activity Relationship
PubMed: 33582388
DOI: 10.1016/j.ejmech.2021.113243 -
Pakistan Journal of Pharmaceutical... May 2020Chemotherapy, radiotherapy, surgery and depression are the conditions that run in parallel fashions. All these conditions cause the release of an increased amount of...
Chemotherapy, radiotherapy, surgery and depression are the conditions that run in parallel fashions. All these conditions cause the release of an increased amount of serotonin in the body. Serotonin acts on these 5HT3 receptors and causes nausea and vomiting. Ondansetron acts by blocking serotonin from acting on the receptors and thus is useful in decreasing episodes of nausea and vomiting but when used concomitantly with SSRIs (selective serotonin reuptake inhibitors) as cancer patient also suffered from depression. This combination tends to decrease the efficacy of ondansetron. The present study was carried out to observe the modulatory role of ondansetron on ileal smooth muscle motility in vitro. Experiments were performed in four groups (n=6) and ileal smooth muscle activity was recorded on the power lab (USA). The effects of increasing concentrations of serotonin, ondansetron and paroxetine alone were observed. In the fourth group effects of paroxetine in the presence of fixed concentration (1ml) of ondansetron (10M) was observed. The maximum response obtained by serotonin served as a control for our study (100%). Paroxetine response on intestinal motility was completely blocked in the presence of ondansetron. Our findings hence, reinforce the hypothesis that paroxetine decreases the antiemetic activity of serotonin antagonist ondansetron, by super sensitization of serotonergic receptors resulting in an increased incidence of nausea and vomiting in cancer patient despite adequate antiemetic prophylaxis.
Topics: Animals; Antiemetics; Drug Interactions; Female; Gastrointestinal Motility; Ileum; Male; Muscle, Smooth; Nausea; Ondansetron; Paroxetine; Rabbits; Receptors, Serotonin; Serotonin Antagonists; Selective Serotonin Reuptake Inhibitors; Vomiting
PubMed: 33191244
DOI: No ID Found -
Biomedicine & Pharmacotherapy =... Apr 20195-HTR antagonists such as ondansetron, granisetron and tropisetron have been clinically used to treat nausea and vomiting in chemotherapy patients. However, current... (Review)
Review
5-HTR antagonists such as ondansetron, granisetron and tropisetron have been clinically used to treat nausea and vomiting in chemotherapy patients. However, current study and research revealed novel potentials of these ligands in other diseases like inflammation, Alzheimer's, and drug abuse. Towards utilising these drugs as anti-smoking agents to treat nicotine dependence problem, there are conflicting reports regarding the potential of these ligands in modulating the effects of nicotine in both human and animal behavioural studies. This is complicated by the heterogeneity of 5-HTR itself, cross regulation between nicotinic acetylcholinergic receptor (nAChR) and distinct pharmacological profiles of 5-HTR antagonists. This review gathered existing studies conducted investigating the potential of "-setron" class of 5-HTR antagonists in modulating nicotine effects. We proposed that the mechanism where 5-HTR antagonists mediate the effects of nicotine could be attributed by both direct at 5-HTR and indirect mechanism in nicotine addiction downstream regulation. The indirect mechanism mediated by the 5-HTR antagonist could be through α7 nAChR, 5-HT receptor (5-HTR), 5-HT receptor (5-HTR), calcineurin activity, p38 MAPK level, PPAR-γ and NF-κβ. Our review suggested that future studies should focus on newer 5-HTR antagonist with superior pharmacological profile or the one with multitarget action rather than high selectivity at single receptor.
Topics: Humans; Palonosetron; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists; Tobacco Use Disorder
PubMed: 30797147
DOI: 10.1016/j.biopha.2019.108630 -
Journal of Labelled Compounds &... Jun 2015Serotonin 2A receptors have been implicated in various psychophysiological functions and disorders such as depression, Alzheimer's disease, or schizophrenia. Therefore,... (Review)
Review
Serotonin 2A receptors have been implicated in various psychophysiological functions and disorders such as depression, Alzheimer's disease, or schizophrenia. Therefore, neuroimaging of this specific receptor is of significant clinical interest, and it is not surprising that many attempts have been made to develop a suitable 5-HT2A R positron emission tomography-tracer. In this review, we give an overview on the precursor, reference compound synthesis, and the preparation of promising 5-HT2A R radiopharmaceuticals applied in positron emission tomography. We also highlight possible learning outcomes that can be made from these tracer development processes.
Topics: Positron-Emission Tomography; Radiopharmaceuticals; Receptor, Serotonin, 5-HT2A; Serotonin Antagonists
PubMed: 25997728
DOI: 10.1002/jlcr.3288 -
ACS Chemical Neuroscience Feb 2024Rapid adenosine transiently regulates dopamine and glutamate via A receptors, but other neurotransmitters, such as serotonin, have not been studied. In this study, we...
Rapid adenosine transiently regulates dopamine and glutamate via A receptors, but other neurotransmitters, such as serotonin, have not been studied. In this study, we examined the rapid modulatory effect of adenosine on serotonin release in the dorsal raphe nuclei (DRN) of mouse brain slices by using fast-scan cyclic voltammetry. To mimic adenosine release during damage, a rapid microinjection of adenosine at 50 pmol was applied before electrical stimulation of serotonin release. Transient adenosine significantly reduced electrically evoked serotonin release in the first 20 s after application, but serotonin release recovered to baseline as adenosine was cleared from the slice. The continuous perfusion of adenosine did not change the evoked serotonin release. Surprisingly, the modulatory effects of adenosine were not regulated by A receptors as adenosine still inhibited serotonin release in AKO mice and also after perfusion of an A antagonist (8-cyclopentyl-1,3-dipropyl xanthine). The inhibition was also not regulated by A receptors as perfusion of the A antagonist (MRS 1220) in AKO brain slices did not eliminate the inhibitory effects of transient adenosine. In addition, adenosine also inhibited serotonin release in AKO mice, showing that A did not modulate serotonin. However, perfusion of a selective 5HT autoreceptor antagonist drug [(S)-WAY 100135 dihydrochloride] abolished the inhibitory effect of transient adenosine on serotonin release. Thus, the transient neuromodulatory effect of adenosine on DRN serotonin release is regulated by serotonin autoreceptors and not by adenosine receptors. Rapid, transient adenosine modulation of neurotransmitters such as serotonin may have important implications for diseases such as depression and brain injury.
Topics: Mice; Animals; Serotonin; Dorsal Raphe Nucleus; Adenosine; Serotonin Antagonists; Receptors, Serotonin
PubMed: 38336455
DOI: 10.1021/acschemneuro.3c00687 -
CNS Drugs Jan 2017Alzheimer's disease (AD) is the most common cause of dementia in elderly people. Because of the lack of effective treatments for this illness, research focused on... (Review)
Review
Alzheimer's disease (AD) is the most common cause of dementia in elderly people. Because of the lack of effective treatments for this illness, research focused on identifying compounds that restore cognition and functional impairments in patients with AD is a very active field. Since its discovery in 1993, the serotonin 5-HT receptor has received increasing attention, and a growing number of studies supported 5-HT receptor antagonism as a target for improving cognitive dysfunction in AD. This article reviews the rationale behind investigations into the targeting of 5-HT receptors as a symptomatic treatment for cognitive and/or behavioral symptoms of AD. In addition to describing the available clinical evidence, this article also describes the purported biochemical and neurochemical mechanisms of action by which 5-HT receptor antagonists could influence cognition, and the preclinical data supporting this therapeutic approach to AD. A large number of publications describing the development of ligands for this receptor have come to light and preclinical data indicate the procognitive efficacy of 5-HT receptor antagonists. Subsequently, the number of patents protecting 5-HT chemical entities has continuously grown. Some of these compounds have successfully undergone phase I clinical studies and have been further evaluated in clinical phase II trials with variable success. Phase II studies have also revealed the potential of combining 5-HT receptor antagonism and cholinesterase inhibition. Two of these antagonists, idalopirdine and RVT-101, have been further developed into ongoing phase III clinical trials. Overall, 5-HT receptor antagonists can reasonably be regarded as potential drug candidates for the treatment of AD.
Topics: Alzheimer Disease; Animals; Clinical Trials as Topic; Humans; Receptors, Serotonin; Serotonin Antagonists
PubMed: 27914038
DOI: 10.1007/s40263-016-0399-3 -
Cell Oct 2015Flibanserin acts at cortical, limbic, hypothalamic, and brainstem nuclei to inhibit serotonin release by binding to 5-HT1A autoreceptors and block postsynaptic action of...
Flibanserin acts at cortical, limbic, hypothalamic, and brainstem nuclei to inhibit serotonin release by binding to 5-HT1A autoreceptors and block postsynaptic action of serotonin at 5-HT2A receptors. This gradually disinhibits the turnover of other monoamines like dopamine and noradrenaline that are critical for sexual desire.
Topics: Benzimidazoles; Brain; Humans; Receptors, Serotonin; Serotonin Antagonists; Sexual Dysfunctions, Psychological
PubMed: 26496594
DOI: 10.1016/j.cell.2015.10.015 -
Expert Opinion on Pharmacotherapy 2015Hypoactive sexual desire disorder (HSDD) is the most common form of female sexual dysfunction (FSD). Some theories suggest that HSDD has a neurobiological component... (Review)
Review
INTRODUCTION
Hypoactive sexual desire disorder (HSDD) is the most common form of female sexual dysfunction (FSD). Some theories suggest that HSDD has a neurobiological component linked to neurotransmitter imbalances. Flibanserin is the only FDA-approved treatment of HSDD; before its approval, the disorder was often left untreated or interventions were made using evidence-based psychological methods or 'off-label' use of bupropion, testosterone and other dopaminergic agents.
AREAS COVERED
Flibanserin, a multifunctional serotonin agonist/antagonist, is approved as a nonhormonal option designed specifically for the treatment of HSDD. Flibanserin has been shown to cause statistically significant increases in the number of satisfying sexual events and in sexual desire scores on standardized/validated measures while reducing FSD-related distress of premenopausal women diagnosed with HSDD. Similar efficacy has been demonstrated in a smaller group of postmenopausal women also affected by HSDD. The side effects of flibanserin include dizziness, somnolence, nausea and (rarely) syncope, and are comparable to other CNS drugs.
EXPERT OPINION
While there has been debate over the approval of flibanserin for treatment of HSDD, it is evident that flibanserin provides meaningful relief to women suffering from a common sexual dysfunction and is an important addition to the field of women's health.
Topics: Animals; Benzimidazoles; Clinical Trials, Phase III as Topic; Female; Humans; Libido; Premenopause; Serotonin Antagonists; Serotonin Receptor Agonists; Sexual Dysfunctions, Psychological
PubMed: 26395164
DOI: 10.1517/14656566.2015.1090426 -
Journal of Medicinal Chemistry Sep 2021In line with recent clinical trials demonstrating that ondansetron, a 5-HT receptor (5-HTR) antagonist, ameliorates cognitive deficits of schizophrenia and the known...
In line with recent clinical trials demonstrating that ondansetron, a 5-HT receptor (5-HTR) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT receptor (5-HTR) antagonists, we applied the hybridization strategy to design dual-acting 5-HT/5-HTR antagonists. We identified the first-in-class compound , which behaves as a 5-HTR antagonist and a neutral antagonist 5-HTR of the Gs pathway. shows selectivity over 87 targets and decent brain penetration. Likewise, inhibits phencyclidine (PCP)-induced hyperactivity and displays procognitive properties in the novel object recognition task. In contrast to , neither 5-HTR inverse agonist SB399885 nor neutral 5-HTR antagonist CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HTR antagonism and 5-HTR antagonism, exemplified by , contributes to alleviating the positive-like symptoms. Present findings reveal critical structural features useful in a rational polypharmacological approach to target 5-HT/5-HT receptors and encourage further studies on dual-acting 5-HT/5-HTR antagonists for the treatment of psychiatric disorders.
Topics: Animals; Antipsychotic Agents; Cognitive Dysfunction; Drug Combinations; Guinea Pigs; Humans; Male; Microsomes, Liver; Molecular Structure; Nootropic Agents; Ondansetron; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists; Structure-Activity Relationship; Sulfonamides
PubMed: 34467765
DOI: 10.1021/acs.jmedchem.1c00224