Current Pharmaceutical Design - Volume 16, Issue 5, 2010

Schizophrenia is a chronic, severe, and disabling brain disorder characterized by a profound disruption of perception, cognition, and emotion. The condition affects approximately 1% of the population and is thought to be the result of genetic vulnerability and environmental influences. The symptoms of schizophrenia fall into three main categories, i.e. positive symptoms (hallucinations, delusions), negative symptoms (apathy, lack of emotion) and cognitive symptoms (problems with attention, certain types of memory, and executive functions). Antipsychotic medications available effectively alleviate the positive symptoms of schizophrenia. However, negative symptoms and cognitive deficits remain poorly treated and are considered to belong to a core syndrome in schizophrenia. For this reason, investigators are developing more effective medications and using new research tools to understand the causes of schizophrenia and to find better ways to prevent and treat it. The present issue provides a state of the art review of some of these new pharmacological approaches in this rapidly expanding area. Mailman and Murthy provide an historical overview of antipsychotic medication and describe functional selectivity at D2 dopamine receptors as a novel mechanism of antipsychotic drug action [1]. The new concept of functional selectivity posits that a ligand may inherently produce a mix of effects through a single receptor depending on the effector pathway coupled to that receptor [2]. Thus, it is conceivable that a ligand or drug might target not the receptor alone, but a receptor-directed signaling complex. With regard to antipsychotic drug action, it was envisaged that if dopamine D2 autoreceptors could be preferentially activated with a dopamine agonist, then dopaminergic transmission might be diminished, which could lead to a functional dopamine antagonist-like effect. In theory, therefore, a low dose of a full agonist could be used to decrease dopamine release, thereby causing benefit in schizophrenia. Lopez-Gil and co-workers have studied the cortical glutamatergic and serotonergic transmission in an animal model of schizophrenia based on NMDA hypofunction [3]. The results suggest that serotonergic transmission in the prefrontal cortex is regulated by the concurrent participation of multiple monoamine receptors, whereas glutamatergic transmission is strongly dependent on dopamine D2-like receptor activation. Thus, although further testing of newer antipsychotics is warranted, it seems that so-called atypical antipsychotic drugs are able to block increases in cortical glutamate and serotonin elicited by a NMDA receptor antagonist. However, classical antipsychotics appear to block only the increased glutamatergic transmission. Based on a large study with selective agonist and antagonist compounds for which antipsychotic drugs possess some affinity, these authors propose that dopamine D2 receptor antagonists would increase cortical GABAergic inhibition whereas other monoaminergic compounds (5-HT2A and α1- adrenergic antagonists as well as 5-HT1A agonist) would be helpful in reducing an excessive excitatory transmission in the prefrontal cortex. McCreary and Jones report on the beneficial effects of serotonin 5-HT1A receptor agonists in the alleviation of symptoms of schizophrenia [4]. There is growing interest in 5-HT1A receptors as potential targets for antipsychotic drug action [5]. Indeed, a series of studies using the 5- HT1A partial agonists tandospirone and buspirone have reported a modest ability of these agents to improve some domains of cognition in patients receiving typical or atypical antipsychotic drugs. However, it remains to be determined whether these compounds act on presynaptic or postsynaptic 5-HT1A receptors. Postsynaptic 5-HT1A receptors are highly expressed in the hippocampus, frontal cortex, entorhinal cortex and the amygdala, all of which have been implicated in various features of schizophrenia. Preclinical studies have evidenced that 5-HT1A receptors located in the prefrontal cortex seem to be crucial for the ability of atypical (but not classical) antipsychotics to increase cortical dopamine release, an effect potentially involved in the improvement of negative symptoms and cognitive dysfunction in schizophrenia. Tsai and co-workers [6] have dealt with the importance of increasing NMDA receptor mediated glutamatergic transmission in the treatment of schizophrenia [7]. This therapy is directly based upon the hypothesis that the illness is caused by an impaired glutamatergic transmission at NMDA receptors. These authors report a meta-analysis of the efficacy and side effects, in schizophrenia treatment, of agents that enhance NMDA receptor neurotransmission via their action at the NMDA receptor-associated glycine (Gly) site. Overall, although NMDA-enhancing agents as a group show promise in improving some of the symptoms of schizophrenia when added to stable antipsychotic treatment, they do not seem to be an option as a sole pharmacological treatment of the illness. Finally, Hajos and Rogers provide a timely review of α7 nicotinic acetylcholine receptors [8], which is an important area of potential therapeutics in schizophrenia because α7 nicotinic partial agonists have been shown to exhibit pro-cognitive and antipsychotic actions [9]. The high level of expression of this receptor within the limbic circuitry, including hippocampus and prefrontal cortex is in line with their purported involvement in cognitive functions. The stimulation of α7 nicotinic acetylcholine receptors by agonists or positive allosteric modulators is believed to activate impaired GABA transmission, thus leading to a restitution of gamma-frequency oscillations. However, a considerable advance in this field has been done in the preclinical setting and there are only very limited data on the cognitive effects of such compounds in humans. Overall the contributions of this special issue provide a valuable opportunity for a multidisciplinary discussion of approaches to increase our knowledge of the complex pharmacology of antipsychotic medications. All the papers in this issue have been subjected to a peer review process. Thanks are given to the Editorial Board and referees who have helped to produce this issue.

Functional selectivity is the term that describes drugs that cause markedly different signaling through a single receptor (e.g., full agonist at one pathway and antagonist at a second). It has been widely recognized recently that this phenomenon impacts the understanding of mechanism of action of some drugs, and has relevance to drug discovery. One of the clinical areas where this mechanism has particular importance is in the treatment of schizophrenia. Antipsychotic drugs have been grouped according to both pattern of clinical action and mechanism of action. The original antipsychotic drugs such as chlorpromazine and haloperidol have been called typical or first generation. They cause both antipsychotic actions and many side effects (extrapyramidal and endocrine) that are ascribed to their high affinity dopamine D2 receptor antagonism. Drugs such as clozapine, olanzapine, risperidone and others were then developed that avoided the neurological side effects (atypical or second generation antipsychotics). These compounds are divided mechanistically into those that are high affinity D2 and 5-HT2A antagonists, and those that also bind with modest affinity to D2, 5-HT2A, and many other neuroreceptors. There is one approved third generation drug, aripiprazole, whose actions have been ascribed alternately to either D2 partial agonism or D2 functional selectivity. Although partial agonism has been the more widely accepted mechanism, the available data are inconsistent with this mechanism. Conversely, the D2 functional selectivity hypothesis can accommodate all current data for aripiprazole, and also impacts on discovery compounds that are not pure D2 antagonists.

The systemic administration of noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists has been considered as a pharmacological model of schizophrenia. In the present work, we used in vivo microdialysis to examine: first, the effects of MK-801, on the efflux of glutamate and serotonin (5-HT) in the medial prefrontal cortex (mPFC) of the rat; second, whether the MK-801-induced changes in the cortical efflux of both transmitters could be blocked by atypical (clozapine and olanzapine) and classical (haloperidol and chlorpromazine) antipsychotic drugs given intra-mPFC; and third, the role of local blockade of dopamine D2/D3/D4, serotonin 5-HT2A and α1-adrenergic receptors as well as agonism at dopamine D1/D5 and 5-HT1A receptors in the mPFC on the increased efflux of glutamate and 5-HT elicited by MK-801. The four antipsychotic drugs blocked the MK-801-induced increase in glutamate, whereas only clozapine and olanzapine were able to block the increased efflux of 5-HT. Furthermore, M100907 (5-HT2A antagonist), BAY x 3702 (5-HT1A agonist) and prazosin (α1-adrenergic antagonist) blocked the MK-801-induced increase of 5-HT and glutamate in the mPFC. In contrast, raclopride (D2/D3 antagonist) and L-745,870 (D4 antagonist) were able to prevent the increased efflux of glutamate (but not that of 5-HT) elicited by MK-801. SKF-38393 (dopamine D1/D5 agonist) also prevented the MK-801-induced increase of glutamate in the mPFC, but the same effect on cortical 5-HT was reached only at the highest concentration tested. We suggest that the blockade of an exacerbated 5- HT release in the mPFC induced by NMDA antagonists can be a characteristic of atypical antipsychotic drugs. Moreover, we propose that D2/D3/D4 receptor antagonists would act predominantly on a subpopulation of GABAergic interneurons of the mPFC, thus enhancing cortical inhibition, which would prevent an excessive glutamatergic transmission. Dopamine D1/D5 agonists would further stimulate GABA release from other subpopulation of interneurons controlling cortical output to the dorsal raphe nucleus. Atypical antipsychotic drugs might further act upon 5-HT2A, 5-HT1A and α1-adrenoceptors present in pyramidal cells (including those projecting to the dorsal raphe nucleus), which would directly inhibit an excessive excitability of these cells.

Schizophrenia is a complex psychiatric disorder characterised by positive and negative symptoms, cognitive impairments, attentional problems, anxiety and depressive symptoms. The use of atypical antipsychotics has generally improved clinical outcome yet medical need remains. The potential use of 5-HT1A receptor agonism is emerging as one potential area that could be exploited to improve clinical management of the disease. 5-HT1A receptor agonism will not reduce hyperprolactinaemia but does appear to enhance effects on positive, negative and cognitive symptoms and also treat attentional, depressive and anxiety symptoms whilst reducing the extrapyramidal side effect profile, compared to classical antipsychotic agents. Agonism at the 5-HT1A receptor might therefore offer potential benefits to the pallet of existing strategies for the treatment of schizophrenia. We review existing data in support of this. However, further clinical data are needed to prove these hypotheses.

Although hypofunction of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission is proposed to play an important role in the pathophysiology of schizophrenia, results of the clinical trials of small molecules that enhance the NMDA function are inconsistent. A meta-analysis of all the double-blind, placebo-controlled studies in patients with schizophrenia was performed to examine their efficacy on different symptom domains, the dose-response, the effects of concomitant antipsychotics, and their side effects. About eight hundred subjects from 26 studies were included in current meta-analysis. Overall, the NMDA-enhancing molecules are effective in most schizophrenic symptom domains with the effect size (ES) of total psychopathology of 0.40 (p< 1x10-4). The ES of clinical efficacy of the symptom domains were in the order of depressive (0.40, p=3x10-4), negative (0.38, p< 1x10-4), cognitive (0.28, p=2x10-3), positive symptom (0.26, p=0.0006), and general psychopathology (0.26, p=0.006). Glycine, D-serine, and sarcosine treatments significantly improved multiple symptom domains, whereas D-cycloserine did not improve any symptom domain. Moderator analysis revealed that glycine, D-serine and sarcosine are better than D-cycloserine in improving the overall psychopathology. Patients receiving risperidone or olanzapine, but not clozapine, improved. No significant side effect or safety concern was noted. In addition to testing more lead compounds, long-term trials are required to determine their functional improvement capacity. Other drug targets that may enhance NMDA neurotransmission other than the molecules tested so far need to be explored.

The most abundant homomeric nicotinic acetylcholine receptors (nAChRs) in the mammalian brain are the pentameric α7 nAChRs which consist of five α7 subunits, and each subunit provides an orthosteric low affinity binding site for its endogenous ligand, acetylcholine. Distribution and high level expression of α7 nAChRs within the limbic circuitry, including the hippocampus and prefrontal cortical areas are in line with their involvement in various cognitive functions. Activation of α7 nAChRs generates a conformational change of sub-unit proteins, making the channel permeable to cations, in particular calcium, leading to change in neuronal activity and excitability, and via increased intracellular calcium, modulating transmitter release and neuronal network activity. Since genetic linkage studies implicated the α7 nAChRs subunit gene CHRNA7 in schizophrenia, there is a considerable interest for developing drug therapies targeting α7 nAChRs. In this review recent development of selective agonists and positive allosteric modulators of α7 nAChRs are discussed. In addition to summarizing medicinal chemistry efforts, both cellular and neuronal network pharmacology of α7 nAChRs are covered. The association between CHRNA7 gene and impaired P50 auditory gating has provided an attractive endophenotype, and its use as a potential translational biomarker for α7 nAChRs drug discovery is discussed. Preliminary clinical findings on α7 nAChRs agonists are also summarized.

Broad-spectrum antibiotics, directed against conserved bacterial targets, are the mainstay of antibacterial therapy. Increasing resistance, however, demands new strategies. Over time a number of therapeutic concepts have evolved, starting out with the use of polyclonal antisera, which were rapidly replaced by the easier to use antibiotics. Other concepts, such as immunotherapy, radioimmunotherapy, anti-virulence agents, phage therapy and others are under evaluation and often limited in application. In the discovery process of new antibiotics in the pharmaceutical industry quite a number of new agents have emerged, which exhibit a surprisingly high degree of species-specificity. None of them has been considered for development so far. Some examples from the literature which show selectivity for Helicobacter pylori, Pseudomonas aeruginosa, Haemophilus influenzae, Staphylococcus aureus, anaerobes, and others, will be discussed here. It is postulated that there is a room for such agents in future antibacterial therapy, e.g. in difficult to treat infections caused by nonfermenters such as multiresistant P. aerugoinosa, Acinetobacter, Enterobacteriaceae, and S.aureus, including MRSA. Their application would include monotherapy as well as combination therapy with other antibiotics, antivirulence agents or immunotherapy and these possibilities would greatly expand the current anti-infective armamentarium.

The case for peptide-based drugs is compelling. Due to their chemical, physical and conformational diversity, and relatively unproblematic toxicity and immunogenicity, peptides represent excellent starting material for drug discovery. Nature has solved many physiological and pharmacological problems through the use of peptides, polypeptides and proteins. If nature could solve such a diversity of challenging biological problems through the use of peptides, it seems reasonable to infer that human ingenuity will prove even more successful. And this, indeed, appears to be the case, as a number of scientific and methodological advances are making peptides and peptide-based compounds ever more promising pharmacological agents. Chief among these advances are powerful chemical and biological screening technologies for lead identification and optimization, methods for enhancing peptide in vivo stability, bioavailability and cell-permeability, and new delivery technologies. Other advances include the development and experimental validation of robust computational methods for peptide lead identification and optimization. Finally, scientific analysis, biology and chemistry indicate the prospect of designing relatively small peptides to therapeutically modulate so-called ‘undruggable’ protein-protein interactions. Taken together a clear picture is emerging: through the synergistic use of the scientific imagination and the computational, chemical and biological methods that are currently available, effective peptide therapeutics for novel targets can be designed that surpass even the proven peptidic designs of nature.