Current Pharmaceutical Design - Volume 21, Issue 26, 2015

Neuropsychiatric disorders represent a substantial social and health care issue. The National Institutes of Health estimates that greater than 2 million adults suffer from neuropsychiatric disorders in the USA. These individuals experience symptoms that can include auditory hallucinations, delusions, unrealistic beliefs and cognitive dysfunction. Although antipsychotic medications are available, suboptimal therapeutic responses are observed for approximately one-third of patients. Therefore, there is still a need to explore new pharmacotherapeutic strategies for the treatment of neuropsychiatric disorders. Many of the medications that are used clinically to treat neuropsychiatric disorders have a pharmacological profile that includes being an antagonist at D2-like (D2, D3 and D4) dopamine receptor subtypes. However, dopamine receptor subtypes are involved in a variety of neuronal circuits that include movement coordination, cognition, emotion, affect, memory and the regulation of prolactin. Consequently, antagonism at D2-like receptors can also contribute to some of the adverse side effects associated with the long-term use of antipsychotics including the a) adverse extrapyramidal symptoms associated with the use of typical antipsychotics and b) metabolic side effects (weight gain, hyperglycemia, increased risk of diabetes mellitus, dyslipidemia and gynecomastia) associated with atypical antipsychotic use. Preclinical studies suggest that D3 versus D2 dopamine receptor selective compounds might represent an alternative strategy for the treatment of the symptoms of schizophrenia. In this review we discuss a) how bitropic Nphenylpiperazine D3 dopamine receptor selective compounds have been developed by modification of the primary (orthosteric) and secondary (allosteric or modulatory) pharmacophores to optimize D3 receptor affinity and D2/D3 binding selectivity ratios and b) the functional selectivity of these compounds. Examples of how these compounds might be modified to develop bivalent ligands capable of interacting with receptor dimers or oligomers are also provided. Preclinical studies using bitropic D3 dopamine receptor selective ligands are also discussed as strategy to pharmacologically dissect the role of the D2 and D3 dopamine receptor subtypes in animal models of neuropsychiatric, neurological and substance abuse disorders. This research has the potential to a) advance the understanding of the role of the D2 and D3 dopamine receptor subtypes in neuropsychiatric disorders and b) lead to new treatment strategies for neuropsychiatric disorders.

Schizophrenia is characterised by positive, negative, cognitive, depressive and anxiety symptoms. Over the last decades a number of novel treatment strategies with better clinical efficacy and scope, but with lower side-effect profiles have been developed. These have significantly improved the management and prognosis of the disease. Of these approaches, modulation of the serotonergic receptor system is a common, recurring, theme; particularly the use of 5-HT1A receptor agonism as part of or adjunct to existing therapies. Here we review data exploring the utility of 5-HT1A receptor agonists for extending the actions of antipsychotic agents, while limiting their side-effect profile. Notably, interest has grown concerning 5-HT1A receptor activation in schizophrenia because of the development of novel antipsychotics, such as lurasidone and cariprazine, the characterisation of 5-HT1A receptor polymorphisms in schizophrenia patients and the possible beneficial influence of 5-HT1A agonists on neurogenesis.

It is now well accepted that receptors can regulate cellular signaling pathways in the absence of a stimulating ligand, and inverse agonists can reduce this ligand-independent or “constitutive” receptor activity. Both the serotonin 5-HT2A and 5-HT2C receptors have demonstrated constitutive receptor activity in vitro and in vivo. Each has been identified as a target for treatment of schizophrenia. Further, most, if not all, atypical antipsychotic drugs have inverse agonist properties at both 5-HT2A and 5-HT2C receptors. This paper describes our current knowledge of inverse agonism of atypical antipsychotics at 5-HT2A/2C receptor subtypes in vitro and in vivo. Exploiting inverse agonist properties of APDs may provide new avenues for drug development.

5-hydroxytryptamine6 receptor (5-HT6R) antagonists have shown efficacy in animal models for cognitive impairment in multiple cognitive domains relevant for schizophrenia. Improvements were found with 5-HT6R antagonists in preclinical tests for episodic memory, social cognition, executive function, working memory and several other tests for both learning and memory. In contrast, there is little evidence for efficacy on attention. It will be interesting to further investigate 5-HT6R antagonists in neurodevelopmental animal models which are based on prenatal exposure to specific environmental insults, and are characterized by a high level of face, construct and predictive validity for cognitive impairments associated with schizophrenia. It is also important to do more add-on preclinical studies of 5-HT6 antagonists with antipsychotics. Possible mechanisms of action to improve cognition have been described. 5-HT6R antagonists decrease GABA release and GABAergic interneuron excitability, which subsequently disinhibits glutamate and/or acetylcholine release and results in enhancement of synaptic plasticity. Furthermore, cognition could be improved by 5-HT6R antagonists, because these compounds increase the number of NCAM PSA-immunoreactive neurons in the dendate gyrus, inhibit mTOR and Fyn-tyrosine kinase and interact with DARPP-32. Interestingly, there is increasing preclinical evidence that could support additional benefits of 5-HT6R ligandson comorbid conditions in schizophrenia such as drug abuse, depression, anxiety, obesity andantipsychotic-induced EPS. Finally, we briefly give an overview of the 5-HT6R compounds that are currently in clinical development for the treatment of cognitive impairment in both schizophrenia and Alzheimer’s disease.

In spite of almost 60 years of experience with the pharmacological treatment of schizophrenia, there is still a large unmet medical need for better control of especially the negative and cognitive symptoms of schizophrenia. One potential new avenue is the selective blockade of histamine H3 receptors (H3R). Based on a large basis of preclinical data, H3R antagonists or inverse agonists have been suggested to improve cognition in a variety of neurological and psychiatric indications. The aim of the present paper is to review the potential usefulness of H3R antagonists for the treatment of schizophrenia. Although, so far no H3R antagonist has been marketed and many phase II and III studies are still underway, the available data seem to indicate that H3R antagonists may not be primarily effective against the positive symptoms (i.e. the psychotic symptoms such as hallucinations and delusions) but may hold a promise as add-on therapy for selectively improving cognitive and perhaps negative symptoms.

While pharmacological blockade of dopamine D2 receptor can effectively suppress the psychotic or positive symptoms of schizophrenia, there is no satisfactory medication for the negative and cognitive symptoms of schizophrenia in spite of the proliferation of second generation antipsychotic drugs. Excitements over a new class of third generation antipsychotics that might possibly fill this urgent medical need have been prompted by the recent development of glycine transporter 1 (GlyT1) inhibitors. The impetus of this novel pharmacological strategy stems directly from the prevailing hypothesis that negative and cognitive symptoms are attributable to the hypofunction of glutamatergic signalling via the N-methyl-D-aspartate (NMDA) receptor in the brain. Inhibition of GlyT1 reduces clearance of extra-cellular glycine near NMDA receptor-containing synapses, and thereby increases baseline occupancy of the glycine-B site at the NR1 subunit of the NMDA receptor, which is a prerequisite of channel activation upon stimulation by the excitatory neurotransmitter glutamate. Pharmacological inhibition of GlyT1 is expected to boost NMDA receptor function and therefore alleviate persistent negative and cognitive symptoms without excessive risk of excitotoxicity associated with direct NMDA receptor agonists. The recently completed phase III clinical trials of the Roche compound, bitopertin (a.k.a. RG1678 or RO-4917838) had initially raised hope that this new class of drugs might represent the first successful translation of the glutamate hypothesis of schizophrenia to the clinic. However, the outcomes of the multi-centre bitopertin clinical trials have been disappointing. The present review seeks to examine this promise through a critical survey of the latest clinical and preclinical findings on the therapeutic potential of GlyT1 inhibition or down-regulation.

Pomaglumetad methionil (LY2140023) is a mGlu2/3 receptor agonist prodrug reported in 2007 to possess antipsychotic efficacy based on results of a phase 2 trial conducted entirely in Russia using in-patients with schizophrenia. Since that time, pomaglumetad methionil failed to demonstrate antipsychotic efficacy compared to placebo in three phase 2 or phase 3 trials, despite risperidone separating from placebo in one phase 3 trial. While there was some evidence of an antipsychotic effect in these studies on an a priori specified genetically-defined subpopulation based on single nucleotide polymorphisms of the 5-hydroxytryptamine2A receptor gene (HTR2A) , these effects were modest when compared to very limited effects in the overall population of schizophrenic patients responding to SOC second generation antipsychotic drugs. Post-hoc analyses also suggested antipsychotic efficacy for pomaglumetad methionil in subjects with a disease duration equal/less than 3 years or subjects previously treated with antipsychotic drugs predominantly acting at dopamine D2 receptors compared to 5-HT2A receptors. Orthogonal to these results with the mGlu2/3 receptor agonist prodrug, a 5-HT2A receptor inverse agonist pimavanserin demonstrated antipsychotic efficacy in subjects with Parkinson’s disease (PD) psychosis despite limited and at best modest evidence of antipsychotic efficacy for a number of selective 5-HT2A receptor antagonists in subjects with schizophrenia. Based on the precedent for pimavanserin in PD psychosis, the known overlapping preclinical profile of mGlu2/3 receptor agonists and 5-HT2A receptor antagonists/inverse agonists and the neurobiology of other psychosis associated with neurodegenerative illness, there remains open a hypothesis that mGlu2/3 receptor agonists may exert clinically significant antipsychotic effects in PD psychosis, dementia with Lewy Bodies, and Alzheimer’s disease psychosis.

Accumulating evidence suggests that the α7 subtype of nicotinic acetylcholine receptors (nAChRs) plays a key role in inflammatory processes, thought to be involved in the pathophysiology of neuropsychiatric diseases, such as schizophrenia and Alzheimer’s disease. Preclinical and clinical studies showed that the diminished suppression of P50 auditory evoked potentials in patients with schizophrenia may be associated with a decreased density of α7 nAChRs in the brain. This points to a role for auditory sensory gating (P50) as a translational biomarker. A number of agonists and positive allosteric modulators (PAMs) for α7 nAChR promoted beneficial effects in animal models with sensory gating and cognitive deficits. Additionally, several clinical studies showed that α7 nAChR agonists could improve suppression in auditory P50 evoked potentials, as well as cognitive deficits, and negative symptoms in patients with schizophrenia. Taken together, α7 nAChR presents as an extremely attractive therapeutic target for schizophrenia. In this article, the author discusses recent findings on α7 nAChR agonists such as DMXB-A, RG3487, TC-5619, tropisetron, EVP-6124 (encenicline), ABT-126, AQW051 and α7 nAChR PAMs such as JNJ-39393406, PNU- 120596 and AVL-3288 (also known as UCI-4083), and their potential as therapeutic drugs for neuropsychiatric diseases, such as schizophrenia.

There is a wealth of evidence that various neuropeptides and their receptor ligands modulate schizophrenia- related behaviors in preclinical animal models, suggesting that neuropeptide systems may represent potential novel therapeutic targets for the treatment of schizophrenia. In particular, neurotensin and tachykinins have been the subject of significant research efforts, generating compelling preclinical data in the schizophrenia field. However, clinical studies with notably selective tachykinin NK3 receptor antagonists in schizophrenia have been disappointing, and they were unable to confirm the promising therapeutic potential from animal studies, thereby questioning the therapeutic utility of these compounds for this condition. This article reviews preclinical and clinical findings on ligands for neurotensin and tachykinin receptors in schizophrenia, and provides possible explanations for the failure so far to develop small-molecule neuropeptide ligands for the treatment of schizophrenia.

No pharmacological treatment is available to date that shows satisfactory effects on cognitive symptoms in patients diagnosed with schizophrenia. Phosphodiesterase inhibitors (PDE-Is) improve neurotransmitter signaling by interfering in intracellular second messenger cascades. By preventing the breakdown of cAMP and/or cGMP, central neurotransmitter activity is maintained. Different PDE families exist with distinct characteristics among which substrate specificity and regional distribution. Preclinical data is promising especially with regard to inhibition of PDE2, PDE4, PDE5 and PDE10. In addition, cognitive improvement has been reported in both elderly and/or non-impaired young human subjects after PDE1 or PDE4 inhibition. Moreover, some of these studies show effects on cognitive domains relevant to schizophrenia, in particular memory. The current review incorporates an overview of the distinct molecular characteristics of the different PDE families and their relationship to the neurobiological mechanisms related to cognitive dysfunction in schizophrenia. So far, procognitive effects of only three types of PDE-Is have been assessed in patients diagnosed with schizophrenia inhibiting PDE3, PDE5 and PDE10. However, the limited data available do not allow to draw firm conclusions on the value of PDE-Is as cognitive enhancers in schizophrenia yet. The field is still in its infancy, but nevertheless different PDE-Is seem promising as candidate to optimise neural communication in the prefrontal cortex favouring cognitive functioning in patients diagnosed with schizophrenia, in particular dual inhibitors including PDE1-Is, PDE3-Is and PDE10A-Is.

Atrial fibrillation and gastro-oesophageal reflux are common manifestations in daily practice. The atria and the oesophagus are closely located and have similar nerve innervations. Over the last years, it has been observed that atrial fibrillation development and reflux disease could be related. Atrial fibrillation occurrence could be due to vagal nerve overstimulation. This, in association with vagal nerve-mediated parasympathetic stimulation, has also been observed in patients with gastro-oesophageal reflux. These mechanisms, in addition to inflammation, seem to be implicated in the pathophysiology of both diseases. Despite these associations supported by clinical and experimental studies, this relationship is still considered controversial. This review summarizes critical data regarding the association of gastro-oesophageal reflux and atrial fibrillation as well as their clinical implications.

Background. Andolast is a new airway specific anti-inflammatory agent. The aim of the present multicentered, randomized, placebo controlled study is to investigate whether andolast produces a therapeutic response greater than placebo in asthmatic adult patients. Methods. 549 symptomatic patients with mild or moderate asthma were randomized to receive andolast at three different doses (2, 4, or 8 mg t.i.d.) or placebo for 12 weeks. Efficacy and safety were evaluated during scheduled visits with pulmonary function tests, peak expiratory flow rate (PEFR), symptoms diary and quality of life questionnaire. The primary outcome included the changes (expressed as percent variation) from baseline of the forced expiratory volume in one second (FEV1) absolute values after 12 weeks of treatment. Findings. One hundred and thirty one (131) patients were treated with andolast at the dose of 2 mg t.i.d., 128 patients at the dose of 4 mg t.i.d., 144 at the dose of 8 mg t.i.d. and 146 with placebo. Andolast produced a dose dependent significant improvement over placebo on airflow obstruction, as shown by the changes in FEV1 (andolast 2, 4, 8 mg vs. placebo: p = 0.011), especially in a subgroup of patients showing moderate airways obstruction (FEV1<80%pred). The mean number of asthma control days and free days significantly increased, the average number of inhaled puffs of short-acting α2-agonists used as rescue medication was significantly reduced as compared with placebo. Andolast also significantly decreased the incidence of asthma exacerbation episodes. Conclusion. Andolast proved to be significantly more effective than placebo in improving airflow, and in controlling asthma symptoms both during day and night.

We have evaluated the safety and efficacy of intracoronary human umbilical cord-derived mesenchymal stem cell (hUCMSC) treatment for very old patients with coronary chronic total occlusion. hUCMSCs could improve in the degree of ischemic myocardium, decrease in the infarct size and rise in left ventricular ejection fraction, but the involved mechanisms remain to be fully identified. We analyzed levels of circulating leukocytes, highsensitivity C-reactive protein (hs-CRP), interleukins (ILs), tumor necrosis factor-a (TNF-a), soluble tumor necrosis factor receptor-1 (sTNFR-1), soluble tumor necrosis factor receptor-2 (sTNFR-2), NT-proBNP, BNP, angiotensin 1-7 (Ang1-7), angiotensin II (Ang II) and aldosterone (Ald) in patients with hUCMSC therapy at baseline, 12, and 24 months. Levels of Ang1-7, IL-10, IL-37 and IL-17 were increased at 12 months and 24 months; leukocytes, hs- CRP, IL-1