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CNS Neuroscience & Therapeutics 2009Vilazodone (EMD 68843; 5-{4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide hydrochloride) is a combined serotonin specific reuptake inhibitor... (Review)
Review
Vilazodone (EMD 68843; 5-{4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide hydrochloride) is a combined serotonin specific reuptake inhibitor (SSRI) and 5-HT1A receptor partial agonist currently under clinical evaluation for the treatment of major depression. This molecule was designed based on the premise that negative feedback circuitry, mediated via 5-HT1 receptors, limits the acute SSRI-induced enhancements in serotonergic neurotransmission. If the hypothesis is correct, combination of SSRI with 5-HT1A partial agonism should temporally enhance the neuroplastic adaptation and subsequently hasten therapeutic efficacy compared to current treatments. Preclinical in vitro evaluation has confirmed vilazodone's primary pharmacological profile both in clonal and native systems, that is, serotonin reuptake blockade and 5-HT1A partial agonism. However, in vivo and in contrast to combination of 8-OH-DPAT and paroxetine, vilazodone selectively enhanced serotonergic output in the prefrontal cortex of rats. Behavioral evaluations, in the ultrasonic vocalization model of anxiety in rats, demonstrated anxiolytic efficacy. In the forced swim test (a putative model of depression), vilazodone also showed efficacy but at a single dose only. In man, vilazodone abolished REM sleep and demonstrated clinical antidepressant efficacy equivalent to an SSRI. Ongoing clinical evaluations will hopefully reveal whether the founding hypothesis was valid and if vilazodone will produce a more rapid onset of antidepressant efficacy.
Topics: Animals; Antidepressive Agents; Benzofurans; Humans; Indoles; Mood Disorders; Piperazines; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Agonists; Serotonin Plasma Membrane Transport Proteins; Serotonin Receptor Agonists; Selective Serotonin Reuptake Inhibitors; Vilazodone Hydrochloride
PubMed: 19499624
DOI: 10.1111/j.1755-5949.2008.00067.x -
Journal of Smooth Muscle Research =... Feb 20095-Hydroxytryptamine (5-HT) released from enterochromaffin cells regulates gastrointestinal function in either an excitatory or inhibitory manner. 5-HT(3) and 5-HT(4)... (Review)
Review
5-Hydroxytryptamine (5-HT) released from enterochromaffin cells regulates gastrointestinal function in either an excitatory or inhibitory manner. 5-HT(3) and 5-HT(4) receptors in the gut have been the focus of clinical studies on the management of gastrointestinal motility disorders. 5-HT stimulates intestinal propulsive reflexes through 5-HT(4) receptors. 5-HT(4) receptor agonists can stimulate upper or lower gut motility, depending on their selectivity and affinity. In the guinea pig colon, the distribution of 5-HT(4) receptors in the myenteric plexus and circular muscle layer differs between the proximal and distal regions. 5-HT stimulates intestinal motility via excitatory neurons while causing relaxation of the circular muscle via 5-HT(4) receptors. In the light of these findings on the distribution of 5-HT(4) receptors, the effects of receptor agonist compounds could vary depending on the species of experimental animal and the anatomical region studied.
Topics: Animals; Colon; Enterochromaffin Cells; Gastrointestinal Motility; Guinea Pigs; Humans; Receptors, Serotonin, 5-HT3; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists
PubMed: 19377270
DOI: 10.1540/jsmr.45.25 -
Drug Design, Development and Therapy 2023Migraine is a common neurological disorder that is present in a large proportion of the global population. It is estimated to occur in around 20.7% of women and 10.7% of... (Review)
Review
Migraine is a common neurological disorder that is present in a large proportion of the global population. It is estimated to occur in around 20.7% of women and 10.7% of men in the United States. The pathophysiology of migraine is a major focus of research, and medications have been developed to interrupt the processes that generate headache and other bothersome symptoms of migraine attacks. The triptan class of medications acts as a direct agonist at the 5-HT1B/D receptor but its use is limited by contraindications for those with coronary or cerebrovascular disease. Lasmiditan is a first-in-class agonist at the 5-HT1F serotonin receptor that does not appear to generate vasoconstriction. This article reviews the design, development, and place in therapy for lasmiditan. A narrative review of the literature using the Ovid MEDLINE database was performed. The rationale behind the development of lasmiditan and pre-clinical, proof-of-concept, Phase II, pivotal, Phase III trials and post-hoc data is covered. Additionally, the efficacy and safety of lasmiditan when compared to other acute treatments in migraine is described, including lasmiditan's side effect profile and status as a Schedule V substance. Further, head-to-head studies of lasmiditan compared with other acute treatments are required.
Topics: Male; Adult; Humans; Female; Serotonin Receptor Agonists; Piperidines; Pyridines; Migraine Disorders; Treatment Outcome
PubMed: 37426628
DOI: 10.2147/DDDT.S380440 -
Bioorganic & Medicinal Chemistry Letters Oct 2014The dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporter releasing activity and serotonin-2A (5-HT2A) receptor agonist activity of a series of...
The dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporter releasing activity and serotonin-2A (5-HT2A) receptor agonist activity of a series of substituted tryptamines are reported. Three compounds, 7b, (+)-7d and 7f, were found to be potent dual DA/5-HT releasers and were >10-fold less potent as NE releasers. Additionally, these compounds had different activity profiles at the 5-HT2A receptor. The unique combination of dual DA/5-HT releasing activity and 5-HT2A receptor activity suggests that these compounds could represent a new class of neurotransmitter releasers with therapeutic potential.
Topics: Dopamine; Dose-Response Relationship, Drug; Humans; Molecular Structure; Norepinephrine; Receptor, Serotonin, 5-HT2A; Serotonin; Serotonin 5-HT2 Receptor Agonists; Structure-Activity Relationship; Tryptamines
PubMed: 25193229
DOI: 10.1016/j.bmcl.2014.07.062 -
Regulatory Toxicology and Pharmacology... Apr 2020Prucalopride, a high affinity, selective serotonin type 4 (5-HT) receptor agonist, was associated with increased neoplasia incidence (in endocrine tissues and liver) in... (Review)
Review
Prucalopride, a high affinity, selective serotonin type 4 (5-HT) receptor agonist, was associated with increased neoplasia incidence (in endocrine tissues and liver) in 2-year rodent bioassays, without evidence of a genotoxic mechanism of action. Proposed mechanisms of action involve prolactin and the constitutive androstane receptor (CAR). Epigenetic mechanisms and their relevance to humans are discussed. Data from in vitro and in vivo rodent studies demonstrated that prucalopride-related stimulation of prolactin secretion (via dopamine receptor D2 antagonism at high doses) is a rodent-specific, non-genotoxic mechanism for inducing hyperplasia and neoplasia in prolactin receptor-expressing endocrine tissues. Additional data demonstrated that CAR-mediated liver enzyme induction underlies the observed hepatocellular adenomas and thyroid follicular adenomas in rodents. A 12-month neonatal mouse carcinogenicity study confirmed the lack of a genotoxic mechanism of action. Furthermore, tumors were observed only at very high exposures (200 and 63 fold higher in mice and rats, respectively, than human exposure after a daily therapeutic dose of 2 mg). The studies indicate that non-genotoxic, rodent-specific, epigenetic mechanisms that are considered clinically irrelevant are responsible for the increased incidence of neoplasias associated with very high exposure to prucalopride in rodents, and that prucalopride does not pose a carcinogenic safety risk to humans.
Topics: Animals; Benzofurans; Endocrine Gland Neoplasms; Humans; Liver Neoplasms; Receptors, Serotonin, 5-HT4; Risk Assessment; Serotonin 5-HT4 Receptor Agonists
PubMed: 31972188
DOI: 10.1016/j.yrtph.2020.104586 -
CNS Drug Reviews 20015-HT1B autoreceptors are involved in the control of extracellular 5-HT levels from both the terminal and cell body regions of serotonergic neurons. In this manuscript we... (Review)
Review
5-HT1B autoreceptors are involved in the control of extracellular 5-HT levels from both the terminal and cell body regions of serotonergic neurons. In this manuscript we review the pharmacological and pharmacokinetic data available for the selective and potent 5-HT1B receptor inverse agonist, SB-236057-A (1'-ethyl-5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazolyl-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro (furo[2,3-f]indole-3,4'-piperidine) hydrochloride). SB 236057-A has been shown to have high affinity for human 5-HT1B receptors (pK(i) = 8.2) and displays 80 or more fold selectivity for the human 5-HT1B receptor over other 5-HT receptors and a range of additional receptors, ion channels and enzymes. In functional studies at human 5-HT1B receptors SB-236057-A displayed inverse agonism (pA(2) = 8.9) using [(35)S]GTPgammaS binding, and silent antagonism (pA(2) = 9.2) using cAMP accumulation. SB-236057-A also acted as an antagonist at the 5-HT terminal autoreceptor as measured by [3H]5-HT release from electrically stimulated guinea pig and human cortical slices. In the guinea pig, pharmacokinetic analysis demonstrated that SB-236057-A was bioavailable and according to in vivo pharmacodynamic assays it enters brain and has a long duration of action. Importantly no side effect liability was evident at relevant doses from anxiogenic, cardiovascular, sedative or migraine viewpoints. In vivo microdialysis studies demonstrated that SB-236057-A is an antagonist in the guinea pig cortex but has no effect on extracellular 5-HT levels per se. In contrast, SB-236057-A increased extracellular 5-HT levels in the guinea pig dentate gyrus. This increase in 5-HT release was comparable to that observed after 14 days of paroxetine administration. SB-236057-A has been a useful tool in confirming that, in either guinea pigs or humans, the terminal 5-HT autoreceptor is of the 5-HT1B subtype. It appears that acute 5-HT1B receptor blockade, by virtue of increased 5-HT release in the dentate gyrus, may provide a rapidly acting antidepressant.
Topics: Animals; Autoreceptors; Brain; Cyclic AMP; Humans; Hypothermia; Indoles; Microdialysis; Paroxetine; Pyridines; Radioligand Assay; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Selective Serotonin Reuptake Inhibitors
PubMed: 11830759
DOI: 10.1111/j.1527-3458.2001.tb00209.x -
Journal of Clinical Pharmacology Aug 2022Felcisetrag (formerly known as TAK-954) is a selective serotonin receptor agonist under investigation for use in patients with postoperative gastrointestinal... (Clinical Trial)
Clinical Trial
Felcisetrag (formerly known as TAK-954) is a selective serotonin receptor agonist under investigation for use in patients with postoperative gastrointestinal dysfunction. The safety, tolerability, and pharmacokinetics (PK) of intravenous (i.v.) felcisetrag have been studied, but little is known about the effect of hepatic impairment on the PK of the drug. This phase 1, non-randomized, open-label study compared the PK of a single 60-minute i.v. infusion of felcisetrag between healthy individuals (n = 8) and patients with moderate (n = 10) or severe (n = 7) hepatic impairment. The primary study end points were the total and free maximum observed plasma concentration of felcisetrag at the end of infusion (C ), area under the concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC ), and AUC from time 0 to infinity (AUC ). Concentration-time profiles of felcisetrag were similarly shaped between groups but revealed lower concentrations of total plasma felcisetrag with increasing severity of hepatic impairment, whereas concentrations of free felcisetrag increased. The ratios of AUC and AUC for patients with severe hepatic impairment were up to 29.3% lower for total felcisetrag and up to 29.2% higher for free felcisetrag than found in healthy individuals (P < .05). Infusions were well tolerated with no discontinuations, severe adverse events, or deaths during the study. Overall, the effect of hepatic impairment on exposure to felcisetrag was minimal, suggesting that dose adjustment may be unnecessary in patients with hepatic impairment.
Topics: Area Under Curve; Humans; Liver Diseases; Serotonin Receptor Agonists; Severity of Illness Index
PubMed: 35253917
DOI: 10.1002/jcph.2044 -
Nature Structural & Molecular Biology Jul 2022Serotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell...
Serotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell signaling. There are 12 serotonergic G protein-coupled receptor members encoded in the human genome, of which the 5-hydroxytryptamine (5-HT) receptor (5-HTR) is the least understood and lacks selective tool compounds. Here, we report four high-resolution (2.73-2.80 Å) structures of human 5-HTRs, including an inactive state structure bound to an antagonist AS2674723 by crystallization and active state structures bound to a partial agonist lisuride and two full agonists, 5-carboxamidotryptamine (5-CT) and methylergometrine, by cryo-EM. Leveraging the new structures, we developed a highly selective and potent antagonist for 5-HTR. Collectively, these findings both enhance our understanding of this enigmatic receptor and provide a roadmap for structure-based drug discovery for 5-HTR.
Topics: Humans; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists
PubMed: 35835867
DOI: 10.1038/s41594-022-00796-6 -
Drug News & Perspectives Nov 2007Modulating activity at the 5-HT(2C) receptor holds a tremendous amount of therapeutic promise in multiple psychiatric indications. However, the signaling and regulation... (Review)
Review
Modulating activity at the 5-HT(2C) receptor holds a tremendous amount of therapeutic promise in multiple psychiatric indications. However, the signaling and regulation of the 5-HT(2C) receptor is highly complex due to multiple signaling pathways and agonist-directed trafficking of this receptor. Moreover, the 5-HT(2C) receptor is differentially regulated via RNA editing in multiple psychiatric disorders and following either pharmacological or environmental manipulation. Direct and indirect data suggest that both agonists and antagonists may provide benefits in several disorders. The current review highlights the underlying complexities of this area and provides the rationale for using 5-HT(2C) agonists in the treatment of both schizophrenia and depressive disorders.
Topics: Animals; Depressive Disorder; Drug Design; Humans; Receptor, Serotonin, 5-HT2C; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Signal Transduction
PubMed: 18176661
DOI: 10.1358/dnp.2007.20.9.1162244 -
Revista Da Associacao Medica Brasileira... 2011This paper reviews involvement of the serotonergic system in the control of food intake and satiety. It is of great interest to understand the relevance of this system... (Review)
Review
This paper reviews involvement of the serotonergic system in the control of food intake and satiety. It is of great interest to understand the relevance of this system for physiological control of energy balance and obesity. Over 35 years of research suggest that serotonin (5-HT) plays an important role in satiety. Thus, the serotonergic system has been a viable target for weight control. The 5-HT has control over hunger and satiety through different receptors with distinct functions. The 5-HT2C receptor may be more important in the relationship between food intake and energy balance. This review will discuss the mechanisms of the serotonergic system involved in the control of food intake and satiety.
Topics: Animals; Eating; Humans; Hunger; Hypothalamus; Neurotransmitter Agents; Obesity; Satiation; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists
PubMed: 21390463
DOI: No ID Found