Serotonin 2A receptor antagonists for treatment of schizophrenia

Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D₂) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia.

Areas covered: Preclinical, clinical and post-mortem studies of the serotonin 5-HT_2A system in schizophrenia are reviewed. The implications of a combined D₂ and 5-HT_2A receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT_2A receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT_2A receptor antagonists for the treatment of schizophrenia.

Expert opinion: 5-HT_2A receptor antagonists appear to assume an intermediate position by being marginally superior to placebo but inferior to conventional antipsychotic drugs. Three previous 5-HT_2A receptor antagonists have been discontinued after Phase II or III trials, and available Phase IIa data on the remaining 5-HT_2A receptor antagonist will need substantial additional validation to be approved as a new treatment strategy against schizophrenia.     

5-HT2C receptor modulators: a patent survey

Importance of the field: The 5-HT_2C receptor is a GPCR and is one of the 14 subtypes that constitute the serotonin receptor family. The 5-HT_2C receptor is exclusively expressed in the CNS where it demonstrates a wide distribution and displays high-affinity interactions with a wide variety of psychiatric medications. Modulators of 5-HT_2C have been implicated as a potential treatment for diseases of significant unmet medical need, including obesity, schizophrenia, depression, anxiety, Parkinson's disease, drug addiction, erectile dysfunction and urinary incontinence. Thus, there is a great interest in developing potent and selective 5-HT_2C receptor modulators.

Areas covered in this review: This review article highlights the research progress in 5-HT_2C receptor modulators published in the patent literature between January 2003 and June 2010, giving emphasis to the medicinal chemist's standpoint.

What the reader will gain: Readers will rapidly gain an overview of the various 5-HT_2C receptor modulators reported in the patent literature in the past 8 years. Furthermore, the readers will learn which structure type can interact with the 5-HT_2C receptor. In addition, the readers will be aware of the pharmaceutical companies that have been the main players in the field.

Take home message: There is substantial evidence supporting the concept that a selective 5-HT_2C receptor modulator should provide benefit in the treatment of a variety of CNS disorders. Although research efforts have identified several promising 5-HT_2C receptor modulators that display high functional selectivity, further clinical efficacy and safety data are needed to prove their actual clinical utility. Therefore, the query for selectively acting 5-HT_2C receptor modulators is still ongoing.     

5-HT7 receptor modulators: a medicinal chemistry survey of recent patent literature (2004 – 2009)

Importance of the field: The 5-HT₇ receptors are discretely localized within the CNS (thalamus, hypothalamus, limbic and cortical regions). The 5-HT₇ receptors are also present in smooth muscle cells from blood vessels and have been reported in gastrointestinal tract as well as in rat lumbar dorsal root and sympathetic ganglia. The 5-HT₇ receptors have been implicated in depression, disorders related to circadian rhythms, pain and migraine. Thus, there is a great interest in developing potent and selective 5-HT₇ receptor modulators.

Areas covered in this review: This review article highlights the research advances published in the patent literature between January 2004 and December 2009, giving emphasis to the medicinal chemist's standpoint.

What the reader will gain: Readers will rapidly gain an overview of the various 5-HT₇ receptor modulators reported in the patent literature in the past 6 years. Furthermore, the readers will learn which structure type can interact with 5-HT₇ receptor and also the different companies that are the main players in the field.

Take home message: Although no 5-HT₇ modulator has entered clinical trials, the development and future use of different agonists and antagonists suitable for use in vivo seem very promising.     

5-HT2 ligands in the treatment of anxiety and depression

Introduction: One third of depressed patients do not respond adequately to conventional antidepressants including the selective serotonin reuptake inhibitors (SSRIs). Therefore, multi-target drugs or augmentation strategies have been developed for the management of SSRIs-resistant patients. In this context, the 5-HT₂ receptor subtypes represent promising targets but their precise roles have yet to be determined.

Areas covered: The aim of this review is to shed some light on the preclinical evidence supporting the use of 5-HT_2A and/or 5-HT_2C receptor antagonists such as antipsychotics, as potential effective adjuncts in SSRIs-resistant depression. This review synthesizes the current literature about the behavioral, electrophysiological and neurochemical effects of 5-HT₂ receptors ligands on the monoaminergic systems but also on adult hippocampal neurogenesis.

Expert opinion: Although studies support the hypothesis that the inactivation of 5-HT_2A and/or 5-HT_2C receptors might be of interest to reinforce different facets of the therapeutic activity of SSRIs, this pharmacological strategy remains debatable notably because of the lack of chronic data in relevant animal models. Conversely, emerging evidence suggests that the activation of 5-HT_2B receptor is required for antidepressant-like activity, opening the way to new therapeutic approaches. However, the potential risks related to the enhancement of monoaminergic neurotransmissions could represent a major concern.     

Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs

Introduction: The introduction of the triptans (5-hydroxytryptamine (5-HT)_1B/1D receptor agonists) was a great improvement in the acute treatment of migraine. However, shortcomings of the triptans have prompted research on novel serotonergic targets for the treatment of migraine.

Areas covered: In this review the different types of antimigraine drugs acting at 5-HT receptors, their discovery and development are discussed. The first specific antimigraine drugs were the ergot alkaloids, consisting of ergotamine, dihydroergotamine and methysergide, which are agonists at 5-HT receptors, but can also bind α-adrenoceptors and dopamine receptors. In the 1990s, the triptans became available on the market. They are 5-HT_1B/1D receptor agonists, showing fewer side effects due to their receptor specificity. In the last years, compounds that bind specifically to 5-HT_1D, 5-HT_1F and 5-HT₇ receptors have been explored for their antimigraine potential. Furthermore, the serotonergic system seems to act in tight connection with the glutamatergic as well as the CGRP-ergic systems, which may open novel therapeutic avenues.

Expert opinion: Although the triptans are very effective in treating migraine attacks, their shortcomings have stimulated the search for novel drugs. Currently, the focus is on 5-HT_1F receptor agonists, which seem devoid of vascular side effects. Moreover, novel compounds that affect multiple transmitter and/or neuropeptide systems that are involved in migraine could be of therapeutic relevance.     

New-generation 5-HT4 receptor agonists: potential for treatment of gastrointestinal motility disorders

Importance of the field: Gastrointestinal (GI) dysmotility is an important mechanism in functional GI disorders (FGIDs) including constipation, irritable bowel syndrome, functional dyspepsia, and gastroparesis. 5-hydroxytryptamine₄ (5-HT₄) receptors are targets for the treatment of GI motility disorders. However, older 5-HT₄ receptor agonists had limited clinical success because they were associated with changes in the function of the cardiac HERG potassium channel.

Areas covered in this review: We conducted a PubMed search using the following key words alone or in combination: 5-HT₄, safety, toxicity, pharmacokinetics, pharmacodynamics, clinical trial, cardiac, hERG, arrhythmia, potassium current, elderly, prucalopride, ATI-7505, and velusetrag (TD-5108), to review mechanisms of action, clinical efficacy, safety and tolerability of three new-generation 5-HT₄ receptor agonists.

What the reader will gain: Prucalopride, ATI-7505, and velusetrag (TD-5108) are highly selective, high-affinity 5-HT₄ receptor agonists that are devoid of action on other receptors within their therapeutic range. Their efficacy has been demonstrated in pharmacodynamic studies which demonstrate acceleration of colonic transit and, to a variable degree, in clinical trials that significantly relieve chronic constipation. Currently available evidence shows that the new 5-HT₄ receptor agonists have safe cardiac profiles.

Take home message: New-generation 5-HT₄ receptor agonists and future drugs targeting organ-specific splice variants are promising approaches to treat GI dysmotility, particularly colonic diseases.     

The discovery and development of vilazodone for the treatment of depression: a novel antidepressant or simply another SSRI?

Introduction: Vilazodone is the newest serotonergic antidepressant to be approved by the FDA for the treatment of major depressive disorder (MDD). Vilazodone is a combined serotonin specific reuptake inhibitor (SSRI) and 5-HT_1A receptor partial agonist. It was originally designed based on the premise that negative feedback circuitry mediated through somatodendritic 5-HT₁ autoreceptors, limits the acute SSRI-induced enhancements in serotonergic neurotransmission. Therefore, the combination of SSRI with 5-HT_1A receptor agonism should temporally enhance the neuroplastic adaptation and subsequently hasten therapeutic efficacy compared to current treatments.

Areas covered: This review provides the history and preclinical development of vilazodone, highlighting the available data on its putative mechanism of action, potential clinical profile and possible areas for differentiation. These preclinical hypotheses will be contextualised with an overview of the key findings from the current clinic data on vilazodone.

Expert opinion: Preclinical data packages on vilazodone have clearly demonstrated its SSRI activity. In isolated in vitro systems, 5-HT_1A receptor agonism has been demonstrated, but the recapitulation of this activity in vivo has been inconclusive. This uncertainty of its in vivo profile has largely translated to the clinical scenario with efficacy and adverse event profiles being similar to that seen with SSRIs in MDD. More in-depth evaluation of the two Phase III studies have also provided some early evidence of differentiation on onset of therapeutic benefit, anxiety measures and improvements in sexual function. Further evaluation of MDD and anxiety patient outcomes is essential to demonstrate if vilazodone is truly a novel therapeutic.     

5-hydroxytryptamine subtype 6 receptor modulators: a patent survey

Importance of the field: Among the GPCR subclasses that have been discovered to date, 5-HT receptors are especially attractive as key biological targets with enormous clinical importance. In particular, during the last decade, the 5-HT₆ receptor has gained increasing attention due to extensive cellular functions. It has also been suggested that its activity can be mediated by inverse agonists.

Areas covered in this review: Summarizing the points listed above, the current review primarily focuses on patent literature within the title field, evolution and trends that have not yet been covered in such depth in other published papers.

What the reader will gain: To obtain a clear understanding of the situation and dynamics within the field of 5-HT₆ ligands, having an obvious pharmaceutical potential in terms of related patents, we provide a comprehensive search through several key patent collections. We have covered promising small molecule compounds which are being evaluated in different clinical trials as well as drugs currently available in the pharmaceutical market. In addition, readers will gain a deep insight into the patent specification, geographic distribution, tendency and patent holders presented.

Take home message: Several of 5-HT₆-targeted compounds are reasonably regarded as powerful drug candidates for the treatment of a range of neuropathological disorders, including Alzheimer's disease and Huntington's disease.     

Sertindole for the treatment of schizophrenia

Importance of the field: Despite considerable progress in the pharmacological treatment of schizophrenia, unmet needs remain concerning refractory patients, as well as improvement of negative symptoms, cognition, quality of life, adherence and tolerability. Sertindole, a second-generation antipsychotic with high affinity for dopamine D₂, serotonin 5-HT_2A, 5-HT_2C, and α₁-adrenergic receptors, is the first phenylindole-derived antipsychotic agent.

Areas covered in this review: Pharmacodynamics, pharmacokinetics, clinical efficacy, safety and cost-effectiveness of sertindole are covered based on a literature review (PubMed) from 1990 to 2010. Pivotal as well as supportive randomized controlled trials are reviewed along with observational and/or naturalistic safety studies.

What the reader will gain: This review of sertindole will allow the reader to determine the place for sertindole in the schizophrenia treatment landscape.

Take home message: Studies conducted so far suggest a beneficial effect of sertindole on positive and negative symptoms as well as on cognition, relapse prevention and quality of life. There is also some evidence for the treatment of refractory patients. Sertindole induces moderate weight gain, with few extrapyramidal symptoms and metabolic changes. More head-to-head comparisons with other second-generation antipsychotics are, however, still needed as well as further clarification on cardiac safety.     

Update on alisporivir in treatment of viral hepatitis C

Introduction: The development of sumatriptan, more than 20 years ago, added substantially to the characterization of 5-hydroxytryptamine (5-HT) receptors and their relevance to acute migraine therapy. Recently, 5-HT_1F receptor agonists, with no vascular effects, have shown efficacy in the treatment of migraines.

Areas covered: This evaluation reviews the recent advances in acute migraine therapy targeting the 5-HT receptor. Specifically, the authors review the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of 5-HT_1F receptor agonists and new formulations of sumatriptan and dihydroergotamine (DHE).

Expert opinion: Lasmiditan, a non-vascular acting 5-HT_1F receptor agonist, is effective in migraine but causes central nervous system-related adverse events, which may considerably limit its clinical use. The efficacy of transdermal sumatriptan is too low for general use in migraine. Intranasal sumatriptan powder could be a step forward compared with oral sumatriptan, but comparative trials are needed. Orally inhaled DHE has a very quick systemic absorption but the onset of effect in migraine is relatively slow with a maximum effect after 2 h. In contrast, orally inhaled DHE results in a low incidence of recurrence. None of these reviewed treatments are likely to fulfill patients' expectations, and the advancement of acute migraine drugs should likely depend on different mechanisms from current 5-HT-related drugs.     

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.     

Zibotentan for the treatment of castrate-resistant prostate cancer

Importance of the field: Patients with prostate cancer who have progression of their disease while on androgen deprivation therapy have limited therapeutic options. Docetaxel is currently the only agent that increases overall survival in patients with metastatic, castration-resistant prostate cancer; additional agents are needed.

Areas covered in this review: This review will describe the importance of endothelin-1 (ET-1) for growth of prostate cancer cells, development of bone metastases, and pain responses; the preclinical data for zibotentan, a specific inhibitor of the ET_A receptor; and the clinical development of atrasentan, a first-generation ET receptor inhibitor, and zibotentan, a more selective inhibitor of the ET_A receptor.

What the reader will gain: Readers will understand the importance of ET-1 as a novel pathway to target for patients with castration-resistant prostate cancer due to its association with prostate cancer growth, metastases to bone, and pain. Readers will learn about the preclinical and clinical development of zibotentan, including the promising Phase II results that have resulted in an extensive Phase III clinical trials program.

Take home message: Modulating the activity of ET-1 through the ET_A receptor is a novel target for treating patients with metastatic, castration-resistant prostate cancer. There are currently three ongoing Phase III trials with zibotentan, a selective ET_A inhibitor, to determine the effect of this agent on overall survival in these patients.     

Prucalopride for constipation

Importance of the field: Chronic constipation has a high prevalence, and current medical and pharmacological therapies do not restore normal bowel function in all patients.

Areas covered in the review: A PubMed search (1965 – 2009) using the following terms alone or in combination: prucalopride, 5-HT₄, R093877, safety, toxicity, pharmacokinetics, pharmacodynamics, transit, cardiac, hERG, arrhythmia, potassium current, elderly.

What the reader will gain: Understanding of the mechanisms of action, safety, efficacy and indications for prucalopride in patients with chronic constipation.

Take home message: Prucalopride is an efficacious and generally safe, new therapeutic option in the management of chronic constipation.     

5-HT6 receptor modulators: a patent update. Part 2. Diversity in heterocyclic scaffolds

Introduction: Among a variety of proteins included in a relatively wide GPCR family, serotonin 5-HT receptors (5-HT₆Rs) are highly attractive as important biological targets with enormous clinical importance. Among this sub-class, 5-HT₆R is the most recently discovered group. Available biological data clearly indicate that 5-HT₆R antagonists can be used as effective regulators in a variety of contexts, including memory formation, age-related cognitive impairments and memory deficits associated with conditions such as schizophrenia, Parkinson's disease (PD) and Alzheimer's disease (AD). Therefore, this receptor has already attracted a considerable attention within the scientific community, due to its versatile therapeutic potential.

Areas covered: The current paper is an update to the comprehensive review article published previously in Expert Opinion on Therapeutic Patents Ivashchenko AV, Ivanenkov YA, Tkachenko SE. 5-Hydroxytryptamine subtype 6 receptor modulators: a patent survey. Expert Opin. Ther. Pat, 2010, 20, 1171-1196. Here, the authors mainly focus on small-molecule compounds – 5-HT₆ antagonists – which have been described in recent patent literature, since the end of 2009. To obtain a clear understanding of the situation and dynamic development within the field of 5-HT₆ ligands, having an obvious pharmaceutical potential in terms of related patents, the authors provide a comprehensive search through several key patent collections. They describe the reported heterocyclic compounds with no sulfonyl moiety in sufficient detail to provide a valuable insight in the 5-HT₆R chemistry and pharmacology. Most of the described compounds are currently classified as multimodal agents with high affinity toward 5-HT₆R.

Expert opinion: Recent progress in the understanding of the 5-HT₆ receptor function and structure includes a suggested constitutive activity for the receptor, development of a number of multimodal small-molecule ligands and re-classification of many selective antagonists as pseudo-selective agents. Several heterocylic structures with or without any basic center provide sufficient supramolecular interactions and show high agonistic/antagonistic activity against 5-HT₆R. Many ‘multitarget' drugs acting, for instance, against several isoforms of 5-HTR, including 5-HT₆R subtype, as well as against dopamine and/or histamine receptors were shown to have beneficial therapeutic effects. At the same time, these ‘unselective' compounds may also increase the side-effect potential. The ensemble of antagonistic activity against 5-HT₆R and inhibition potency against BuChE can be regarded as the most promising basis for the development of effective drugs with a sufficient therapeutic window for the treatment of several neurodegenerative diseases, including AD and PD.     

Idalopirdine as a treatment for Alzheimer’s disease

Introduction: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. Pharmacological treatment of AD involves acetylcholinesterase inhibitors (AChEIs) for mild-to-moderate AD and memantine for severe AD. These drugs provide mainly symptomatic short-term benefits without clearly counteracting the progression of the disease. Idalopirdine is an antagonist of the serotonin 6 (5-HT₆) receptor, which is expressed in areas of the CNS involved with memory. Given that there is evidence suggesting that the blockade of 5-HT₆ receptors induces acetylcholine release, it became reasonable to consider that 5-HT₆ antagonism could also be a promising approach for restoring acetylcholine levels in a deteriorated cholinergic system.

Areas covered: This review discusses the history leading to the discovery of idalopirdine, its pharmacokinetics and pharmacodynamics profile and safety issues, together with an overview of clinical trials carried out so far. A literature search was performed with PubMed using the keywords idalopirdine, AD and 5-HT₆ antagonists. The article is also based on information derived from the ClinicalTrials.gov site for clinical trials with idalopirdine.

Expert opinion: Idalopirdine is safe and well tolerated. It could be used as add-on therapy to potentiate the effect of available AChEIs in AD. Nevertheless, results from ongoing Phase III trials are needed to verify whether this drug has a significant clinical effect on cognition in association with AChEIs.     

Patent Evaluation: Psychotropic Benzodioxan Derivatives

Summary

Novelty: Novel benzodioxan derivatives useful as antipsychotic and anxiolytic agents are disclosed. The compounds are useful in the treatment of a variety of CNS disorders, such as depression, schizophrenia and paranoia.

Biology: The affinity of the compounds for the dopamine D₂ receptor and the serotonin 5-HT_1A receptor were determined according to the methods of Fields (Brain Res. (1977) 136:578) and Hall (J. Neurochem. (1985) 44:1685). One compound gave 83% inhibition for D₂ binding and 100% inhibition for 5-HT_1A binding at 0.1 μM.

Chemistry: Syntheses of the compounds are described in nine examples. N-Methyl-[2-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-amino]ethyltricyclo[3 .3.1.1 (3,7)]-decane-1-carboxamide is one of nine specifically claimed compounds.

Structure:      

5-HT receptors as targets for the development of novel anxiolytic drugs: models,mechanisms and future directions

The introduction of buspirone for the treatment of anxiety, together with the eventual suggestion of a mode of action involving the serotonin (5-HT)_1A receptor subtype, has generated considerable research activity and renewed interest in the potential role of 5-HT in anxiety. The further identification of multiple 5-HT₁ receptors, coupled with the possibility that these subtypes potentially are involved in discrete biobehavioral regulation and pathophysiological conditions, has greatly expanded the search for tools capable of probing these receptors and has raised hopes for a new generation of more specific compounds to treat other disorders associated with the 5-HT system such as depression, aggression, and sleep and eating disturbances. The involvement of 5-HT in anxiety has prompted a careful reevaluation of several traditional areas of research. This has included those methods used in the in vivo evaluation of drugs in preclinical animal test procedures used to assess potential anxiolytic activity, as well as the mechanisms associated with adaptive changes occurring during long-term drug administration. The proliferation of various procedures for studying the anxiolytic effects of 5-HT drugs has not always been accompanied by systematic behavioral and pharmacological validation. At the present time, this area of research is characterized by numerous inconsistent findings. Procedures that are objective and impartial to the behavioral effects of drugs provide distinct advantages for addressing some of these issues, as will the results from carefully controlled clinical studies. The main objective of this article is to provide an overview of the recent developments in research involving the 5-HT system and anxiety. The emphasis will be on the 5-HT₁ receptor system and a review of the results in the predominant animal models used to evaluate these drugs, as well as an overview of the mechanisms currently believed to be responsible for the therapeutic activity of this class of compounds. Studies with the pigeon are reviewed, since this species appears distinctly sensitive to the anxiolytic-like effects of 5-HT_1A drugs in conflict procedures. Although chronic administration of 5-HT_1A drugs appears necessary for clinical anxiolytic and antidepressant activity, the most noteworthy neuropharmacological effects in animals seem to occur in 5-HT₂ and, perhaps, 5-HT₃ receptors which are downregulated. Studies summarizing the activity of drugs interacting with 5-HT_1C/2 and 5-HT₃ receptor sites are also discussed as they too may be involved in anxiety or the actions of anxiolytic drugs. The growing evidence suggesting an interaction between 5-HT receptor types, particularly between 5-HT_1A and 5-HT_1C/2 receptors, is reviewed, since drugs with these combined properties appear to be particularly efficacious in animal models of anxiety and warrant further detailed analyses. The development of drugs targeted specifically at multiple receptors may provide distinct therapeutic advantages for disorders such as anxiety and depression that appear to involve multiple neurotransmitter systems.