5-HT1A receptor ligands and their therapeutic applications: review of new patents

Introduction: 5-HT_1AR was one of the first discovered serotonin receptors and is one of the most thoroughly studied. Dysfunctions associated with 5-HT_1AR neurotransmission are linked to several psychiatric disorders, including anxiety, depression, and movement disorders.

Areas covered: The current review covers patent literature published between January 2012 and May 2018. Queries were performed on Espacenet, SciFinder, clinicaltrials.gov, pharmacodia.com, and the websites of pharmaceutical companies.

Expert opinion: Several novel therapeutic applications have been proposed for 5-HT_1AR ligands, i.e. prostate cancer treatment, gastrointestinal and cardiopulmonary disorders, facilitation of urination and defecation, and L-DOPA-induced dyskinesia. Interestingly, no patent application has been filed by big pharma companies, while numerous researches are being conducted in smaller companies and academia.     

Serotonin receptor targeted therapy for migraine treatment: an overview of drugs in phase I and II clinical development

Introduction: Research has focused on serotonin (5-HT) 5-HT_1D and 5-HT_1F receptors to develop drugs acting through non-vasoconstrictive mechanisms for treating acute migraine and those targeting 5-HT_2B and 5-HT₇ receptors for preventing migraine.

Areas covered: This paper reviews antimigraine drugs targeting 5-HT receptors in one phase I trial (sumatriptan iontophoretic transdermal system, TDS) and five phase II clinical trials (PNU-142633, LY334370, lasmiditan, NOX-188).

Expert opinion: Data from our overview on investigational drugs in phase I and II clinical trials using the 5-HT_1B/1D receptor agonist (sumatriptan TDS), 5-HT_1D receptor agonist (PNU-142633), 5-HT_1F receptor agonists (LY334370, lasmiditan) and a combined 5-HT_1B/1D receptor agonist with nNOS inhibition (NOX-188) provided encouraging data for sumatriptan TDS and lasmiditan, disappointing results for PNU-142633, and promising findings for NOX-188. The 5-HT_1F receptor agonist lasmiditan, a drug acting through non-vasoconstrictive mechanisms, represents a promising safe, effective and tolerated acute migraine therapy also for patients at cardiovascular risk. Upcoming phase III trials should clarify the optimal lasmiditan dose and eventual clinical advantages over triptans. The negative results for the PNU-142633 trial prompt further studies using specific compounds more precisely targeting 5-HT_1D receptors. Antagonism at 5-HT_2B and 5-TH₇ receptors, a promising strategy to prevent migraine, is still limited to experimental migraine models.     

The role of 5 HT6-receptor antagonists in Alzheimer’s disease: an update

Introduction: Despite recent advances in Alzheimer’s disease (AD) research, no breakthrough treatments have been discovered. Cholinesterase inhibitors and the NMDA-receptor antagonist memantine are currently the two approved symptomatic treatments for AD. 5-HT6 receptor antagonism has recently emerged as a promising treatment strategy to improve cognition in AD, with a modest side-effect profile.

Areas covered: 5-HT6 receptors, exclusively found in the central nervous system, modulate primarily GABA and glutamate levels, facilitating the secondary release of other neurotransmitters including dopamine, noradrenaline, and acetylcholine, all of which are compromised in AD. This review discusses findings of preclinical and phase I–III clinical trials conducted with three major 5-HT6 receptor antagonists: idalopirdine, intepirdine, and SUVN-502, in the field of AD.

Expert opinion: Despite early positive findings, larger phase-III trials have failed to demonstrate any statistically significant impact on cognition for both idalopirdine and intepirdine, as adjunct to cholinesterase inhibitors. Paradoxically, 5-HT6 receptor agonists have also been shown to have cognitive enhancing properties. Thus, a better understanding of the mechanism of action of the 5-HT6 receptor and its ligands is warranted. Investigating 5-HT6 receptor partial or inverse agonists may be promising in future AD trials.     

Emerging chemical therapies targeting 5-hydroxytryptamine in the treatment of Alzheimer’s disease

Introduction: Alzheimer’s disease (AD) is a major neuropsychiatric disorder affecting more than 5 million Americans over age 65. By the year 2050, AD is expected to affect over 30 million. Characterized by neuronal cell death accompanied by the accumulation of neurofibrillary tangles and neuritic plaques, AD results in devastating clinical symptomatology with a lasting psychosocial and financial impact. Studies have shown that the current treatments for AD, cholinesterase inhibitors (ChEI’s) and NMDA receptor antagonists, have limited efficacy. The 5-HT-6 receptor antagonists Idalopirdine and Intepirdine have shown the most progress in current clinical trials and warrant consideration as emerging treatments for AD.

Areas covered: This review discusses 5-HT6 antagonists currently in clinical trials as potential treatments for AD symptomatology and how 5-HT6 physiology may play a positive role in alleviating AD symptom pathophysiology. A literature search using PubMed was conducted using the terms Idalopirdine, Intepirdine, 5-HT-6 antagonist, and AD as keywords. Clinicaltrials.gov and Alzforum were also used to obtain information on clinical trials.

Expert opinion: If current Phase-3 trials are positive, 5-HT6 antagonists such as Idalopirdine and Intepirdine may be considered as supplementary treatments to ChEI’s and NMDA receptor antagonists for the symptomatic treatment of AD.     

Pimavanserin: novel pharmacotherapy for Parkinson’s disease psychosis

Introduction: Pimavanserin is the first FDA-approved atypical antipsychotic drug indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (PDP).

Areas covered: This review focuses on the preclinical discovery of pimavanserin. It analyzes the pharmacological, behavioral and molecular mechanisms of pimavanserin and their contribution to the therapeutic advantages of the drug as reported in published preclinical and clinical studies, press releases and product labels.

Expert opinion: Pimavanserin exhibits a unique pharmacological profile with nanomolar affinity at serotonin 5-HT_2A and 5-HT_2C receptors. Functionally, it acts as a potent inverse agonist at 5-HT_2A receptors, with selectivity over 5-HT_2C receptors and no appreciable activity at other neurotransmitter receptors. Behavioral studies found that pimavanserin reversed impaired behaviors in animal models predictive of antipsychotic activity, and with no impairment of motor functions. The drug exhibits long plasma half-life (57 hours), which support its once/day administration. A pivotal phase III clinical trial demonstrated significant improvement in PDP symptoms in patients receiving pimavanserin compared to placebo-treated patients. The drug also displayed relatively benign safety and tolerability profiles. Pimavanserin’s mechanism of action might contribute to its unique psychopharmacological properties in the improved treatment of PDP, and perhaps psychosis in other diseases including schizophrenia and dementia-related psychosis.     

Side effects associated with current and prospective antimigraine pharmacotherapies

Introduction: Migraine is a neurovascular disorder. Current acute specific antimigraine pharmacotherapies target trigeminovascular 5-HT_1B/1D, 5-HT_1F and CGRP receptors but, unfortunately, they induce some cardiovascular and central side effects that lead to poor treatment adherence/compliance. Therefore, new antimigraine drugs are being explored.

Areas covered: This review considers the adverse (or potential) side effects produced by current and prospective antimigraine drugs, including medication overuse headache (MOH) produced by ergots and triptans, the side effects observed in clinical trials for the new gepants and CGRP antibodies, and a section discussing the potential effects resulting from disruption of the cardiovascular CGRPergic neurotransmission.

Expert opinion: The last decades have witnessed remarkable developments in antimigraine therapy, which includes acute (e.g. triptans) and prophylactic (e.g. β-adrenoceptor blockers) antimigraine drugs. Indeed, the triptans represent a considerable advance, but their side effects (including nausea, dizziness and coronary vasoconstriction) preclude some patients from using triptans. This has led to the development of the ditans (5-HT_1F receptor agonists), the gepants (CGRP receptor antagonists) and the monoclonal antibodies against CGRP or its receptor. The latter drugs represent a new hope in the antimigraine armamentarium, but as CGRP plays a role in cardiovascular homeostasis, the potential for adverse cardiovascular side effects remains latent.     

Current Phase II investigational therapies for insomnia

Introduction: Insomnia is typified by a difficulty in sleep initiation, maintenance and/or quality (non-restorative sleep) resulting in significant daytime distress.

Areas covered: This review summarizes the available efficacy and safety data for drugs currently in the pipeline for treating insomnia. Specifically, the authors performed MEDLINE and internet searches using the keywords ‘Phase II’ and ‘insomnia’. The drugs covered target GABAA (zaleplon-CR, lorediplon, EVT-201), orexin (filorexant, MIN-202), histamine-H1 (LY2624803), serotonin 5-HT_2A (ITI-007), melatonin/serotonin5-HT_1A (piromelatine) and melatonin (indication expansions of prolonged-release melatonin and tasimelteon for pediatric sleep and circadian rhythm disorders) receptors.

Expert opinion: Low-priced generic environments and high development costs limit the further development of drugs that treat insomnia. However, the bidirectional link between sleep and certain comorbidities may encourage development of specific drugs for comorbid insomnia. New insomnia therapies will most likely move away from GABA_AR receptors’ modulation to more subtle neurological pathways that regulate the sleep–wake cycle.     

The preclinical discovery and development of cariprazine for the treatment of schizophrenia

Introduction: Cariprazine is approved in the United States and Europe for the treatment of manic or mixed episodes associated with bipolar I disorder and for the treatment of schizophrenia in adult patients. It is typically administered orally once a day (a dose range 1.5 – 6 mg/day), does require titration, and may be given with or without food. It has a half-life of 2 – 4 days with an active metabolite that has a terminal half-life of 2 – 3 weeks.

Areas covered: This review article focuses on the preclinical discovery of cariprazine providing details regarding its pharmacological, behavioral, and neurochemical mechanisms and its contribution to clinical therapeutic benefits. This article is based on the available literature with respect to the preclinical and clinical findings and product labels of cariprazine.

Expert opinion: Cariprazine shows highest affinity toward D₃ receptors, followed by D₂, 5-HT_2B, and 5-HT_1A receptors. It also shows moderate affinity toward σ₁, 5-HT_2A, and histamine H₁ receptors. Long-term administration of cariprazine altered the abundance of dopamine, serotonin, and glutamate receptor subtypes in different brain regions. All these mechanisms of cariprazine may contribute toward its unique preclinical profile and its clinically observed benefits in the treatment of schizophrenia, bipolar mania, and possibly other psychiatric disorders.     

Vortioxetine: a novel antidepressant for the treatment of major depressive disorder

Introduction: Vortioxetine is a novel antidepressant drug approved for the treatment of major depressive disorder (MDD) in adults. It is formulated into tablets and has a dose range of 5–20 mg. The recommended starting dose is 10 mg administered orally once daily without the need for food.

Areas covered: This review focuses on the preclinical and clinical discovery of vortioxetine. It analyzes the pharmacological, neurochemical, and behavioral mechanisms of the medication and how these contribute to its potential therapeutic advantages as described in published preclinical and clinical studies and product labels.

Expert opinion: Vortioxetine displays high affinity for serotonin transporter (SERT), and serotonin 5-HT₃, 5HT_1A, 5HT₇ receptors. Functional studies show that vortioxetine acts as a SERT blocker, a 5-HT₃, 5-HT₇ receptor antagonist, and a 5-HT_1A receptor agonist. The drug is active in animal models predictive of antipsychotic and antidepressant activities and demonstrates procognitive effects in several animal models that assessed memory, cognition, and executive functions. Short- and long-term clinical trials demonstrated the clinical efficacy of vortioxetine in treating depressive symptoms and cognitive deficits in MDD patients. It also displays fairly benign safety and tolerability profiles. Vortioxetine’s unique psychopharmacological properties might contribute to an improved clinical outcome in MDD patient populations.     

The therapeutic potential of novel anti-migraine acute therapies

Introduction: Migraine is a highly disabling neurovascular disorder. ‘The complex and multifactorial properties of migraine pathogenesis provide the opportunity to identify new therapeutic targets from a wide range of receptors.

Areas covered: In this editorial, the authors focus on future pharmacological interventions for acute migraine including: 5-HT receptors and their agonists, calcitonin gene-related peptide receptors and their antagonists, PAC1 receptors and their antagonists, glutamate receptors and some of their antagonists as well as transient receptor potential channels and their antagonists. The authors also discuss preventative treatments for migraine that are currently in development.

Expert opinion: Future pharmaceutical research that looks at the well-known mechanisms involved in the pathophysiology of migraine should aim to overcome the existing limitations of each pharmacological class and their side effects. There has lately been particular interest in the role of glutamate receptors, particularly metabotropic glutamate receptors, in the pathophysiology of migraine. These receptors may be potentially viable drug targets for migraine in the future.     

Neuronal and behavioral plasticity: the role of serotonin and BDNF systems tandem

Introduction: Serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) are known as principal players in different kinds of plasticity. The 5-HT–BDNF interaction in early ontogeny and in adult brain is an intriguing problem.

Area covered: This paper concentrates on the interaction between 5-HT and BDNF systems and its implication in different plasticity levels, from neurons to behavior. This review describes (1) different 5-HT functioning in the embryonic (as neurotrophin) and adult brain (as a neurotransmitter); (2) BDNF as a modulator of 5-HT system and vice versa; (3) the prolonged positive effect of BDNF on genetically and epigenetically defined central nervous system disorders; (4) The 5-HT–BDNF interplay contribution to aggressive behavior, depression, drug addiction, suicide, and stress response; and (5) the role of common second messengers for 5-HT and BDNF signaling in the 5-HT–BDNF interaction.

Expert opinion: Dysregulation in 5-HT–BDNF interaction may be responsible for development of neuropsychiatric and behavioral abnormalities. 5-HT–BDNF cross-talk is a potential target for the treatment of various neurological diseases. Understanding the function of the members of BDNF system in response to challenges of the environment and the interaction with different 5-HT receptors in health and disease will one day lead to new classes of drugs.     

Comparative pharmacokinetics of (S)-MP3950, a novel 5-HT4 receptor agonist,in normal and atropine-induced gastrointestinal motility disorders rats

1. (S)-MP3950 is the (S)-enantiomer of active metabolite of mosapride, which exhibits higher 5-HT₄ receptor agonistic effect than mosapride. It shows promise to become a novel drug candidate for the treatment of gastrointestinal motility disorders (GMDs). However, the pharmacokinetic behavior of (S)-MP3950 in the pathological state of GMDs remains unclear. Herein, we investigated the comparative pharmacokinetics of (S)-MP3950 in normal and GMDs rats.

2. The comparative pharmacokinetics of (S)-MP3950 in normal and atropine-induced GMD rats were studied by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The validated UPLC-MS/MS method was successfully applied to investigate the pharmacokinetic profiles of (S)-MP3950 in normal and atropine-induced GMDs rats. Results showed that comparing to normal rats, C_max reduced by 73.8%, AUC_0-t decreased by 57.6% and AUC_0-∞ declined by 56.8% in model rats. Additionally, the elimination half-life (t_1/2) and T_max were prolonged slightly.

3. The pharmacokinetic results demonstrated that the atropine-induced GMDs reduced the absorption of (S)-MP3950. The pharmacokinetics research in the pathological state might provide more useful information for further study of novel gastric motility candidates.     

Progress in the development of histamine H3 receptor antagonists/inverse agonists: a patent review (2013-2017)

Introduction: Since years, ligands blocking histamine H₃ receptor (H₃R) activity (antagonists/inverse agonists) are interesting targets in the search for new cures for CNS disorders. Intensive works done by academic and pharmaceutical company researchers have led to many potent and selective H₃R antagonists/inverse agonists. Some of them have reached to clinical trials.

Areas covered: Patent applications from January 2013 to September 2017 and the most important topics connected with H₃R field are analysed. Espacenet, Patentscope, Pubmed, GoogleScholar or Cochrane Library online databases were principially used to collect all the materials.

Expert opinion: The research interest in histamine H₃R field is still high although the number of patent applications has decreased during the past 4 years (around 20 publications). Complexity of histamine H₃R biology e.g. many isoforms, constitutive activity, heteromerization with other receptors (dopamine D₂, D₁, adenosine A_2A) and pharmacology make not easy realization and evaluation of therapeutic potential of anti-H₃R ligands. First results from clinical trials have verified potential utility of histamine H₃R antagonist/inverse agonists in some diseases. However, more studies are necessary for better understanding of an involvement of the histaminergic system in CNS-related disorders and helping more ligands approach to clinical trials and the market.

Lists of abbreviations: hAChEI – human acetylcholinesterase inhibitor; hBuChEI – human butyrylcholinesterase inhibitor; hMAO – human monoamine oxidase; MAO – monoamine oxidase     

Pharmacotherapy for generalized anxiety disorder in adult and pediatric patients: an evidence-based treatment review

Introduction: Generalized anxiety disorder (GAD) often begins during adolescence or early adulthood and persists throughout the lifespan. Randomized controlled trials support the efficacy of selective serotonin and selective serotonin norepinephrine reuptake inhibitors (SSRIs and SNRIs, respectively), as well as benzodiazepines, azapirones, anti-adrenergic medications, melatonin analogs, second-generation antipsychotics, kava, and lavender oil in GAD. However, psychopharmacologic treatment selection requires clinicians to consider multiple factors, including age, co-morbidity, and prior treatment.

Areas covered: The authors review the literature concerning pharmacotherapy for pediatric and adult patients with GAD with specific commentary on the efficacy and tolerability of selected agents in these age groups. The authors describe an algorithmic approach to the pediatric and adult patient with GAD and highlight considerations for the use of selected medications in these patients.

Expert opinion: In adults with GAD, SSRIs and SNRIs represent the first-line psychopharmacologic treatment while second-line pharmacotherapies include buspirone, benzodiazepines, SGAs, and pregabalin. In pediatric patients with GAD, SSRIs should be considered the first line pharmacotherapy and psychotherapy enhances antidepressant response.     

Brexpiprazole for the treatment of schizophrenia

Introduction: Limited efficacy on negative and cognitive symptoms and adverse effects of current antipsychotics raise the need of developing new antipsychotics. Brexpiprazole, a new antipsychotic drug approved by the U.S. Food and Drug Administration in July 2015 for the treatment of schizophrenia, is a novel serotonin-dopamine receptor modulator with partial agonist activity at serotonin 1A (5-HT_1A) and D_2/3 receptors.

Areas covered: We reviewed brexpiprazole related in vitro and in vivo studies, including phase II and phase III clinical trials in this article. Brexpiprazole showed significant improvement of psychotic symptoms for patients with schizophrenia in clinical trials. Most of the clinical trials demonstrated the antipsychotic effect of brexpiprazole using Positive and Negative Syndrome Scale (PANSS) in acute schizophrenia patients, and found that higher doses (2–4 mg daily) of brexpiprazole had better outcomes. In short-term trials, brexpiprazole did not show benefit for cognitive function in 6 weeks. Insomnia, akathisia, headache, and agitation were the most frequently recorded adverse events.

Expert commentary: Brexpiprazole showed better efficacy than placebo in acute phase of schizophrenia. Long-term studies are needed to investigate the efficacy of brexpiprazole for cognitive function as well as the strength and weakness of brexpiprazole among current antipsychotic drugs.     

Pharmacotherapy for premature ejaculation

Introduction: Four premature ejaculation (PE) subtypes are distinguished on the basis of the duration of the intravaginal ejaculation latency time (IELT), its course in life, and frequency of complaints. Since the 1930s oral drug treatment and local anesthetics have been used to treat PE. Apart from dapoxetine, all currently available drugs to treat PE (SSRIs, clomipramine, and local anesthetics) are off-label. Not only men with lifelong and acquired PE, but also men with normal IELT values may want to postpone their ejaculation time.

Areas covered: The guideline of the International Society for Sexual Medicine for the treatment of PE has provided evidence-based recommendations for the pharmacotherapy of lifelong and acquired PE. Selective serotonin reuptake inhibitors (SSRIs) delay ejaculation by interfering with the serotonin (5-HT) neurotransmission system in the central nervous system. Attention is given not only to the well-known but also to the recently published, very rare side effects of SSRIs.

Expert opinion: Men with normal IELT values who want to postpone ejaculation do not need “drugs for the treatment of PE” but “ejaculation delaying drugs.” Pharmacological research of these ejaculation-delaying drugs ought to be investigated in men with normal IELT values, such as in men with subjective PE, variable PE, and in male volunteers.     

Evaluation of vilazodone for the treatment of depressive and anxiety disorders

Introduction: Major Depressive Disorder (MDD) and General Anxiety Disorder (GAD) significantly contribute to the global burden of disease. Vilazodone, a combined serotonin reuptake inhibitor and 5-HT1A partial agonist, is an approved therapy for the treatment of MDD and which has been further investigated for GAD.

Areas covered: This article covers the pharmacokinetics and pharmacodynamics of vilazodone and provides an evaluation of the clinical usefulness of vilazodone for the treatment of MDD and anxiety disorders. A literature search was performed using PubMed/MEDLINE, Web of Science and the Cochrane Library.

Expert opinion: Studies have shown that vilazodone is significantly superior to placebo. However, vilazodone cannot as yet be recommended as a first-line treatment option for MDD as it is unclear whether the drug’s dual mechanism of action provides greater efficacy than prevailing treatment options. Moreover, more phase IV studies are needed to establish its efficacy and long-term safety in larger and more diverse populations. Although vilazodone may have an additional advantage for the treatment of anxiety symptoms in MDD, here also additional studies are required to confirm its efficacy over and above SSRI alternatives and other antidepressant treatments. Therefore, presently, vilazodone should be considered as a second- or third-line treatment option for MDD and GAD.     

Efficacy of antidepressants: bias in randomized clinical trials and related issues

Introduction: Countless antidepressant randomized trials were conducted and showed statistically significant benefits of selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) over placebo. Meanwhile, critics are increasing regarding the efficacy of antidepressants in the treatment of MDD because at least a proportion of clinical trials could be hampered by various biases. In contrast, number of failed trials is increasing in the recent years which have made developing psychiatric medications progressively more time-consuming and expensive.

Areas covered: Biases and related issues in clinical trials for antidepressants can be identified as an important common contributing factor to the two paradoxical phenomenon. This review identifies possible biases that can occur before, during, and after clinical trials of antidepressant.

Expert commentary: Recent studies not only may over-estimate efficacy of antidepressants, but also may exaggerate placebo response because of various biases. Sponsorship and publication biases have been one of the targets of the criticism and ethical debate. Thus, initiating new trend of research by re-organizing academic-industry partnership will be the most important task in the next five years.     

Novel leukotriene biosynthesis inhibitors (2012-2016) as anti-inflammatory agents

Introduction: Leukotrienes (LTs) are lipid mediators produced from arachidonic acid with a broad variety of bioactivities in allergy and inflammation. The biosynthesis of LTs mainly involves 5-lipoxygenase (5-LO) and its 5-lipoxygenase-activating protein (FLAP), LTA₄ hydrolase and LTC₄ synthase that all may represent potential targets for LT biosynthesis inhibitors.

Areas covered: We introduce the LT biosynthetic pathway and its cellular regulation, the diverse biological actions of LTs and their receptors, and we briefly describe the pharmacological strategies for suppression of LT formation as well as the classes of current LT biosynthesis inhibitors. The main focus is placed on the comprehensive discussion of recently reported inhibitors of 5-LO, FLAP, LTA₄ hydrolase and LTC₄ synthase, based on literature search (PubMed and Thomson Innovation Patents Searches), covering 2012–2016.

Expert opinion: Although many new series of 5-LO inhibitors have been presented without patenting, essentially by academia, novel FLAP inhibitors (many patented) are most advanced in clinical development and are apparently the focus of pharmaceutical companies. Only few novel inhibitors of LTA₄ hydrolase and LTC₄ synthase were reported. Major issues in the development of LT synthesis inhibitors are related to loss of potency in biological relevant environment, poor pharmacokinetics, lack of oral efficacy, and side effects.