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Pharmacology & Therapeutics Nov 2021Serotonin (5-HT) is one of the fundamental neurotransmitters that contribute to the information essential for an organism's normal, physiological function. Serotonin... (Review)
Review
Serotonin (5-HT) is one of the fundamental neurotransmitters that contribute to the information essential for an organism's normal, physiological function. Serotonin acts centrally and systemically. The 5-HT receptor is the most widespread serotonin receptor, and participates in many brain-related disorders, including anxiety, depression, and cognitive impairments. The 5-HT receptor can activate several different biochemical pathways and signals through both G protein-dependent and G protein-independent pathways. Preclinical experiments indicate that distinct signaling pathways in specific brain regions may be crucial for antidepressant-like, anxiolytic-like, and procognitive responses. Therefore, the development of new ligands that selectively target a particular signaling pathway(s) could open new possibilities for more effective and safer pharmacotherapy. This review discusses the current state of preclinical studies focusing on the concept of functional selectivity (biased agonism) regarding the 5-HT receptor and its role in antidepressant-like, anxiolytic-like, and procognitive regulation. Such work highlights not only the differential effects of targeted autoreceptors, vs. heteroreceptors, but also the importance of targeting specific downstream intracellular signaling processes, thereby enhancing favorable over unfavorable signaling activation.
Topics: Drug Discovery; Forecasting; Humans; Mental Disorders; Serotonin 5-HT1 Receptor Agonists
PubMed: 33905796
DOI: 10.1016/j.pharmthera.2021.107872 -
Scientific Reports May 2022The real-world use of triptans in the treatment of migraine is disappointing. Only 12% of the Danish migraine population purchased a triptan between 2014 and 2019, and...
The real-world use of triptans in the treatment of migraine is disappointing. Only 12% of the Danish migraine population purchased a triptan between 2014 and 2019, and only 43% repurchased a triptan after first prescription. The aim of the present study was to assess whether physicians and patients adhere to the therapeutic guideline on acute migraine treatment. We interviewed 299 triptan experienced participants with migraine and 101 triptan naïve participants with migraine from the Danish Migraine Population Cohort, using a semi-structured questionnaire. Descriptive statistical analyses were used to study the association with triptan use and the assessed factors. Among triptan naïve participants with migraine, 64% had consulted their general practitioner about their migraine, of whom only 23% received information about the possibility of triptan treatment. Among triptan experienced participants, 77% had only tried one type of triptan. Only 12% could recall they had been informed by their general practitioner to try each triptan three times before giving up. Twenty percent were informed to try three different triptans in total, if the first did not work. In disagreement with the guideline, participants who reported a low pain reduction by a triptan had only tried one type of triptan. Our study shows a low adherence to therapeutic guideline for the attack treatment of migraine. There is a need for better education of general practitioners regarding treatment of migraine. Future campaigns should aim to inform both the public and the general practitioner about antimigraine treatments.
Topics: Cohort Studies; Humans; Migraine Disorders; Pain; Serotonin 5-HT1 Receptor Agonists; Tryptamines
PubMed: 35589944
DOI: 10.1038/s41598-022-12545-2 -
Neuropharmacologic studies on the brain serotonin1A receptor using the selective agonist osemozotan.Biological & Pharmaceutical Bulletin 2013Alterations in serotonin (5-HT) neurochemistry have been implicated in the etiology of major neuropsychiatric disorders such as anxiety-spectrum disorders, depression,... (Review)
Review
Alterations in serotonin (5-HT) neurochemistry have been implicated in the etiology of major neuropsychiatric disorders such as anxiety-spectrum disorders, depression, and schizophrenia. The neuromodulatory effects of 5-HT are mediated through 14 receptor subtypes, and those receptors, including the 5-HT1A receptor, are considered to be potential targets for the treatment of psychiatric disorders. We developed the novel 5-HT1A receptor agonist MKC-242 (called osemozotan) and characterized its neurochemical and pharmacological profiles. 5-HT1A receptor agonists modulate the release of amine neurotransmitters through the activation of presynaptic or postsynaptic 5-HT1A receptors in the brain. The agonist has antianxiety and antidepressant effects and improves abnormal behaviors such as aggressive behavior and deficits of prepulse inhibition in isolation-reared mice. We also demonstrated that spinal 5-HT1A receptor activation is involved in isolation rearing-induced hypoalgesia. Concerning the mechanism for induction of isolation-induced abnormal behaviors, we have recently found that the raphe-prefrontal 5-HT system plays a key role in encounter stimulation-induced hyperactivity in isolation-reared mice. Furthermore, we showed that osemozotan attenuates psychostimulant-induced behavioral sensitization and that prefrontal dopamine release is enhanced by functional interaction between the 5-HT1A receptor and other receptors. This review summarizes the neuropharmacology of the 5-HT1A receptor, focusing on our studies using osemozotan, and suggests that the 5-HT1A receptor may be a target molecule for the treatment of psychiatric disorders, pain, and drug dependence.
Topics: Animals; Dioxanes; Dioxoles; Dopamine; Humans; Prefrontal Cortex; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Agonists
PubMed: 24292048
DOI: 10.1248/bpb.b13-00645 -
Biomedicine & Pharmacotherapy =... Dec 2019Serotonin, which also named as 5-hydroxytryptamine (5-HT), is a neurotransmitter, which plays significant roles in a wide range of physiological and pathological... (Review)
Review
Serotonin, which also named as 5-hydroxytryptamine (5-HT), is a neurotransmitter, which plays significant roles in a wide range of physiological and pathological processes. Depression is a complex disease that involves numerous factors, increasing evidences have showed that the level of 5-HT was lower in depressed patients and the administration of some selective serotonin re-uptake inhibitors exhibited antidepressant effects. The 5-HT1A receptor is a key protein in the brain serotonin system, modulating the release of 5-HT and other neurotransmitters. Behavioral and molecular biological studies have demonstrated that the differences of 5-HT1A receptor regulation was connected with depression and the responses to antidepressants. In this review, the authors will introduce the structure and function of 5-HT1A receptor and summarize some antidepressants targeting 5-HT1A receptor, including 5-HT1A receptor agonists and antagonists in a clinic, active ingredients of traditional Chinese medicine. And we found the major of drugs by targeting 5-HT1A receptor on the market or in clinical trials mostly have the similar functional groups, such as piperazine, piperidine, and pyrimidine. There are also some literatures found that these functional groups may be the site produce activity. So, we hope that it may provide basis and references for the research of the clinical drugs for depression.
Topics: Affect; Animals; Antidepressive Agents; Brain; Depression; Drugs, Chinese Herbal; Humans; Medicine, Chinese Traditional; Receptor, Serotonin, 5-HT1A; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Treatment Outcome
PubMed: 31541883
DOI: 10.1016/j.biopha.2019.109408 -
Neuropsychopharmacologia Hungarica : a... Dec 2008Atypical antipsychotics are now widely used in the acute and long-term treatment in bipolar disorder. The role of atypical antipsychotics as acute agents, add-on... (Review)
Review
Atypical antipsychotics are now widely used in the acute and long-term treatment in bipolar disorder. The role of atypical antipsychotics as acute agents, add-on medications; or as primary mood stabilizers in different phases of bipolar disorder is an important current research tendency. However, in bipolar disorder the mostly used indication of quetiapine is the management of acute manic phases, clinical data and the actual research results suggest that it may have both antidepressant and long-term antimanic effects. Quetiapine enhances the transmission of the central serotonergic networks, by its high antagonistic affinity for 5-HT(2A) and partial agonistic activity for the 5-HT(1A) receptors. The 5HT(1A) partial agonism causes an increase in the dopaminergic neurotransmission of the prefrontal cortex, and also, the affinity for the alpha 2-adrenoceptor brings a relative increase in extracellular noradrenergic release an tone in the prefrontal cortex. Latest research shows that quetiapine's main, active, human plasma metabolite, N-desalkyl quetiapine (norquetiapine), has a high inhibition affinity for the noradrenergic transporter. These data suggest that comparing to other atypical antipsychotics, norquetiapine may have a relatively strong antidepressant potential. Modifying the dopaminergic transmission by quetiapine's D2 receptor blocking activity results indirect mediating the cAMP-PKA and the arrestin-Akt-GSK-3 intracellular signal transduction pathways, which process may explain its long-term antimanic and mood stabilizing capability. Quetiapine's activity on nerve growth factors, histamine H1 receptor, proinflammatory networks may take an important additional part in its efficacy in bipolar depression. Its very fast dissociation from the D2 receptor is an important pharmakokinetic parameter for managing the optimal quetiapine dose in the daily clinical practice. This review tries to organize the actual information on quetiapine's multiplex activity in bipolar disorder.
Topics: Adult; Aged; Antidepressive Agents; Antipsychotic Agents; Bipolar Disorder; Brain-Derived Neurotrophic Factor; Dibenzothiazepines; Dopamine; Female; Glutamic Acid; Humans; Male; Middle Aged; Norepinephrine; Quetiapine Fumarate; Receptors, Histamine; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists
PubMed: 19419014
DOI: No ID Found -
Cephalalgia : An International Journal... Apr 2020Triptans are the most commonly used acute treatment for migraine. This study evaluated real-world treatment patterns following an initial triptan prescription to...
BACKGROUND
Triptans are the most commonly used acute treatment for migraine. This study evaluated real-world treatment patterns following an initial triptan prescription to understand refill rates and use of non-triptan medications for the acute treatment of migraine.
METHODS
Commercially-insured adult patients over 18 years of age with a triptan prescription between 1/1/2013 to 31/12/2013 were identified from the Optum Clinformatics™ Data Mart database, with date of the first triptan fill designated as index date. Inclusion was limited to those with no fills for a triptan in the 12 months prior to index date (i.e. new users or initiators of triptans) and continuous enrollment in the 12 months pre- and 24 months post-index date. Fills for index triptan, non-index triptan, and other acute treatments for migraine were assessed for up to 24 months post-index.
RESULTS
Among 10,509 patients, 50.8% did not refill the initial triptan within 12 months and 43.6% did not refill within 24 months. In the 12 months post-index, 90.5% of patients used only one type of triptan, 8.4% used two different triptans, and 1.0% used three or more triptans. Among patients with and without a triptan refill, use of opioids (39% vs. 42%), non-steroidal anti-inflammatory drugs (22% vs. 22%), and butalbital-containing products (9% vs. 10%) were similar.
CONCLUSION
More than half of those who newly initiated a triptan did not refill their initial prescription, and less than 1 in 10 used two or more triptans within 12 months. High rates of non-triptan acute medication use were found over 12 and 24 months of follow-up, most commonly opioids.
Topics: Adolescent; Adult; Aged; Analgesics; Cohort Studies; Female; Humans; Male; Middle Aged; Migraine Disorders; Retrospective Studies; Tryptamines; Young Adult
PubMed: 32138526
DOI: 10.1177/0333102420905307 -
Nuclear Medicine and Biology Mar 2019The serotonin 1B receptor subtype is of interest in the pathophysiology and treatment of depression, anxiety, and migraine. Over recent years 5-HT receptor binding in...
INTRODUCTION
The serotonin 1B receptor subtype is of interest in the pathophysiology and treatment of depression, anxiety, and migraine. Over recent years 5-HT receptor binding in human brain has been examined with PET using radioligands that are partial but not full agonists. To explore how the intrinsic activity of a PET radioligand may affect imaging performance, two high-affinity full 5-HT receptor agonists (AZ11136118, 4; and AZ11895987, 5) were selected from a large compound library and radiolabeled for PET examination in non-human primates.
METHODS
[C]4 was obtained through Pd(0)-mediated insertion of [C]carbon monoxide between prepared iodoarene and homochiral amine precursors. [C]5 was obtained through N-C-methylation of N-desmethyl precursor 6 with [C]methyl triflate. [C]4 and [C]5 were studied with PET in rhesus or cynomolgus monkey. [C]4 was studied with PET in mice and rats to measure brain uptake and specific binding. Ex-vivo experiments in rats were performed to identify whether there were radiometabolites in brain. Physiochemical parameters for [C]4 (pKa, logD and conformational energetics) were evaluated.
RESULTS
Both [C]4 and [C]5 were successfully produced in high radiochemical purity and in adequate amounts for PET experiments. After intravenous injection of [C]4, brain radioactivity peaked at a low level (0.2 SUV). Pretreatment with tariquidar, an inhibitor of the brain P-gp efflux transporter, increased brain exposure four-fold whereas pretreatment with a high pharmacological dose of the 5-HT antagonist, AR-A000002, had no effect on the binding. Ex-vivo experiments in rats showed no radiometabolites entering brain. [C]5 also failed to enter monkey brain under baseline conditions.
CONCLUSIONS
[C]4 and [C]5 show too low brain uptake and specific binding to be useful PET radioligands. Low brain uptake is partly ascribed to efflux transporter action as well as unfavorable conformations.
Topics: Animals; Brain; Chemistry Techniques, Synthetic; Hydrophobic and Hydrophilic Interactions; Image Processing, Computer-Assisted; Ligands; Macaca mulatta; Positron-Emission Tomography; Radiochemistry; Rats; Receptor, Serotonin, 5-HT1B; Serotonin 5-HT1 Receptor Agonists
PubMed: 30811975
DOI: 10.1016/j.nucmedbio.2019.01.005 -
Advances in Therapy Dec 2020Use of triptans for acute treatment of migraine is associated with insufficient efficacy and/or tolerability in approximately 30-40% of people. We conducted a systematic...
INTRODUCTION
Use of triptans for acute treatment of migraine is associated with insufficient efficacy and/or tolerability in approximately 30-40% of people. We conducted a systematic literature review (SLR) to synthesize definitions, terminology, subsequent treatment outcomes, and characteristics associated with this subpopulation.
METHODS
A comprehensive SLR was conducted to identify studies, published from Jan 1995 to May 2019, which focused on insufficient efficacy and/or tolerability to triptans.
RESULTS
Thirty-five publications were identified, of which 22 described randomized controlled trials and open-label studies, and 13 described observational studies. Across studies, multiple objectives and a high amount of variability in methodologies and outcomes were noted. The most commonly applied measures of efficacy were headache pain freedom and pain relief at 2 h. Ten studies assessed efficacy of switching or optimizing treatment in patients with historical insufficient efficacy or tolerability to previous triptan treatment and demonstrated varying levels of success. Factors associated with increased risk of triptan insufficient efficacy included severe baseline headache severity, photophobia, phonophobia, nausea, and depression.
CONCLUSIONS
Irrespective of the methodology or definition used to identify people with insufficient efficacy and/or tolerability to triptans, study results support the assertion that a high unmet need remains for effective acute treatment of migraine.
Topics: Administration, Oral; Adult; Female; Humans; Male; Middle Aged; Migraine Disorders; Nausea; Pain Management; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Severity of Illness Index; Treatment Outcome; Tryptamines
PubMed: 32990921
DOI: 10.1007/s12325-020-01494-9 -
Advances in Therapy Nov 2022Using data from the ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE study in Japan (OVERCOME [Japan]), we describe the current status of the... (Observational Study)
Observational Study
INTRODUCTION
Using data from the ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE study in Japan (OVERCOME [Japan]), we describe the current status of the acute treatment of migraine in Japan.
METHODS
OVERCOME (Japan) was a cross-sectional, observational, population-based web survey of people with migraine in Japan (met modified International Classification of Headache Disorders criteria or had a physician diagnosis of migraine) conducted between July and September 2020. Respondents reported current acute medication use and effectiveness (assessed using the Migraine Treatment Optimization Questionnaire [mTOQ-4]). Cardiovascular history and risk factors of the respondents were also recorded. Potential unmet acute treatment needs were defined as insufficient effect of current acute treatments (mTOQ-4 score ≤ 5), a history of oral triptan use (and not currently taking any triptan), potential contraindications to triptans due to cardiovascular comorbidities, and/or cardiovascular risk factors.
RESULTS
In total, 17,071 people with migraine in Japan completed the survey; 14,869 (87.1%) of these were currently using acute treatments. Poor effectiveness of current acute treatment was reported by 7170 respondents (42.0%), 900 respondents (5.3%) were former triptan users, 1759 (10.3%) had contraindications to triptans, and 9026 (52.9%) reported at least one cardiovascular risk factor. Overall, 12,649 (74.1%) of OVERCOME (Japan) respondents were categorized into one or more of these groups and were considered to have potential unmet acute treatment needs.
CONCLUSION
Almost three-quarters of people with migraine in Japan may have potential unmet needs for acute treatment of migraine. There are substantial opportunities for improving care for people with migraine in Japan, including prescription of novel acute medications.
Topics: Cross-Sectional Studies; Humans; Japan; Longitudinal Studies; Migraine Disorders; Tryptamines
PubMed: 36089637
DOI: 10.1007/s12325-022-02289-w -
Acta Pharmaceutica (Zagreb, Croatia) Jun 2020The introduction of the second generation triptans in clinical and experimental practice was a major progress in the pharmacotherapy of migraine. Frovatriptan is a...
The introduction of the second generation triptans in clinical and experimental practice was a major progress in the pharmacotherapy of migraine. Frovatriptan is a second generation triptan with strong 5-HT1B/1D serotonergic agonism and low 5-HT1A/7 receptor affinity, while almotriptan possesses not only the typical 5-HT1B/1D receptor agonist activity, but shows an affinity to the 5-HT1F receptor. The aim of our study was to assess the impact of frovatriptan and almotriptan on hemodynamics in male and female rats. We used a non-invasive "tail-cuff" method to measure the arterial blood pressure. Female and male Wistar rats were treated separately with high and low dosages of frovatriptan and almotriptan. Male and female rats showed reduction in all hemodynamic parameters, but only male rats showed an increase in the heart rate. In general, we could say that both almotriptan and frovatriptan potentiate cardiovascular safety.
Topics: Animals; Carbazoles; Female; Hemodynamics; Male; Rats; Rats, Wistar; Receptors, Serotonin; Serotonin Receptor Agonists; Tryptamines; Receptor, Serotonin, 5-HT1F
PubMed: 31955146
DOI: 10.2478/acph-2020-0005