Eisai's lemborexant, or E-2006, is a dual orexin OX1/OX2 receptor antagonist (DORA) in codevelopment with Purdue Pharma. Functionally, lemborexant is about 10-fold selective for OX2 over OX1, whereas it is almost nonselective in recombinant human, rat and mouse receptor binding assays. Lemborexant binds and dissociates rapidly from orexin receptors in contrast to other DORAs, which are typically slow to dissociate. It is relatively stable, shows good bioavailability and brain penetration. In mice, lemborexant enhanced sleep for 4-5 h with effects on both non-REM and REM sleep. Lemborexant is currently in phase II/III clinical studies for the treatment of insomnia. A phase II proof-of-concept study investigated six doses from 1 to 25 mg or placebo administered for 15 nights with polysomnography conducted at baseline and on treatment days 1/2 and 14/15. At all doses, lemborexant induced sleep, reduced latency to sleep and wake after sleep onset. Results of other studies have been reported either in abstract form or as corporate press releases. Lemborexant is apparently well tolerated with moderate adverse events, primarily headache and dose-related somnolence. Some studies are placebo controlled, others against active comparators including flurazepam, zolpidem and/or zopiclone where lemborexant was reported as superior to the latter two drugs, especially with respect to next-morning somnolence, driving performance and balance control. Lemborexant is expected to be submitted to regulatory authorities by 2019 and if registered, market forces will tell whether lemborexant fares better than the first-in-class DORA suvorexant and/or selective OX2 receptor antagonists currently in clinical investigation such as seltorexant (JNJ-54717793/MIN-202) or MK-1064.

Methods: Patients attending Sir Charles Gairdner Hospital, Perth who were homozygous for F508del-CFTR and with a ppFEV 1 <40 were monitored for 4 hrs following LUM/IVA initiation.FEV 1 was measured at baseline and at 2-hrs, 1, 3, 6 and 12-months.Antibiotic usage, BMI and adverse events were recorded.Results: In total, 13 adults (median [IQR] ppFEV 1 :34 [31-37]) were initiated with full-dose LUM/IVA and 5 (median [IQR] ppFEV 1: 39 [38-41]) were initiated with half-dose therapy.Patients on full dose therapy experienced a median [IQR] relative decline in ppFEV 1 from baseline at 2-hours of -19 [-21 to -11] whereas the half dose group demonstrated a median [IQR] relative decline of -8 [-12 to -8], p = 0.14.At 12-months, the mean absolute change (n = 8) in FEV 1 was -1.5%, p = 0.40 and in BMI was +1.1, p = 0.11.The median [IQR] number of intravenous (IVAB) antibiotic courses reduced from 2.5 [1-4] in the 12-months pre-therapy to 1 [1-2.75]at 12months, but this was not statistically significant, p = 0.746.Conclusions: There was a trend towards a smaller decline in FEV 1 at 2 hrs post LUM/IVA initiation in patients on half-dose therapy.There were no significant differences in FEV 1 , BMI or IVAB at 12-months with LUM/IVA in patients with advanced lung disease.

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13347/full. This compilation of the major pharmacological targets is divided into eight areas of focus: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates.

Overactivity of glutamate neurotransmission is suspected to be implicated in Parkinson's disease and levodopa-induced dyskinesia. The fast glutamatergic transmission in the striatum from the cortex is mediated mainly by non-n-methyl-d-aspartate (non-NMDA) receptors. Animal models of Parkinson's disease reveal conflicting data concerning striatal glutamate AMPA receptors. The present study thus sought to shed light on the relationship of striatal AMPA receptors to the development of levodopa-induced dyskinesia. [(3)H]Ro 48-8587, a highly potent and selective-specific antagonist ligand for AMPA receptors, was used to investigate, by autoradiography, striatal AMPA receptors in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys treated for 1 month with levodopa alone, levodopa+CI-1041 (NMDA receptor antagonist) or levodopa+cabergoline (D2 receptor agonist). Levodopa-treated MPTP monkeys developed dyskinesias while those that received levodopa+CI-1041 or levodopa+cabergoline did not. In the anterior caudate nucleus and putamen, specific binding of [(3)H]Ro 48-8587 was reduced in all MPTP-treated monkeys compared to control monkeys, but no significant effect of MPTP was measured in the posterior striatum. In dyskinetic monkeys, specific binding of [(3)H]Ro 48-8587 was elevated in subregions of the posterior caudate nucleus and putamen as compared to saline-treated MPTP monkeys. Levodopa+CI-1041 treatment left unchanged specific binding of [(3)H]Ro 48-8587 whereas levodopa+cabergoline treatment reduced it in subregions of the posterior caudate nucleus and putamen compared to control and levodopa-treated MPTP monkeys. Specific binding of [(3)H]Ro 48-8587 was low in the globus pallidus and remained unchanged following both lesion and treatments. In conclusion, the elevated values of AMPA receptors in dyskinetic monkeys (and their prevention through treatments) were only observed in subregions of the striatum.

Neuropeptide receptors represent a large segment of 7 transmembrane domain (7TM) G-protein-coupled receptors expressed in the central nervous system and in the periphery. These receptors are important drug targets for therapies of mental illness, metabolic diseases, and pain. The endogenous ligands are peptides of 5–60 amino acids and thus carry multiple pharmacophores that participate in the agonist action. The development of low molecular weight nonpeptide antagonists has been rapid, while development of low molecular weight agonists has been much more difficult. Despite these difficulties several dozen neuropeptide receptor ligands are in clinical development, as discussed here.

A short overview is given of the evidence supporting the existence of subtypes of 5-HT1 receptors. As 5-HT1 receptors were first described using radioligand binding studies, a brief description of 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptor binding is given. Then, recent data obtained in biochemical, electrophysiological, behavioural and other functional studies is compared to results obtained in radioligand binding studies. The paper shows that functional correlates do indeed exist for subtypes of 5-HT1 recognition sites; moreover, these are markedly different from the effects mediated by 5-HT2 (5-HT D) or 5-HT3 (5-HT M) receptors.

Our knowledge about 5-HT (serotonin, 5-hydroxytryptamine) receptors has gained significantly over the recent few years. The discovery of selective ligands and the use of new techniques have led to a significant increase in the number of recognised receptors subtypes. The present status of awareness is largely related to the use of radioligand binding studies, autoradiography, second messenger analysis and more recently, molecular biological techniques. Three main families of 5-HT receptors, of which subtypes have been described, are now accepted. This heterogeneity is further substantiated by the cloning of the cDNA's of three different 5-HT receptors. This article reviews some of the recent developments which led to the characterisation of 5-HT receptor subtypes.

Formation and extinction of aversive memories in the mammalian brain are insufficiently understood at the cellular and molecular levels. Using the novel metabotropic glutamate receptor 7 (mGluR7) agonist AMN082, we demonstrate that mGluR7 activation facilitates the extinction of aversive memories in two different amygdala-dependent tasks. Conversely, mGluR7 knockdown using short interfering RNA attenuated the extinction of learned aversion. mGluR7 activation also blocked the acquisition of Pavlovian fear learning and its electrophysiological correlate long-term potentiation in the amygdala. The finding that mGluR7 critically regulates extinction, in addition to acquisition of aversive memories, demonstrates that this receptor may be relevant for the manifestation and treatment of anxiety disorders.

Psychiatric and neurological disorders are among the most complex, poorly understood and debilitating diseases in medicine. Abrogating gene function using knockout animals is one of the primary means of examining the pathophysiological significance of a given gene product and has been used successfully in models of neuropsychiatric disorders. However, the developmental compensations that may potentially arise from such approaches are problematic and difficult to assess. The recent discovery of RNAi (RNA interference), as a highly efficient method for gene knockdown, has opened up the possibility for its application in examining the potential role of genes in adult brain function and/or disorders. Recent efforts have focused on applying RNAi-based knockdown to understand the genes implicated in neuropsychiatric disorders. We have developed a method of gene knockdown involving chronic infusion of siRNA (short interfering RNA) using osmotic minipumps. We have silenced a number of genes including those for the serotonin and dopamine transporter. Such tailoring of tools that deliver RNAi in the brain will significantly aid in our understanding of the complex pathophysiology of neuropsychiatric disorders where there is an immensely unmet medical need.

The significant proportion of depressed patients that are resistant to monoaminergic drug therapy and the slow onset of therapeutic effects of the selective serotonin reuptake inhibitors (SSRIs)/serotonin/noradrenaline reuptake inhibitors (SNRIs) are two major reasons for the sustained search for new antidepressants. In an attempt to identify common underlying mechanisms for fast- and slow-acting antidepressant modalities, we have examined the transcriptional changes in seven different brain regions of the rat brain induced by three clinically effective antidepressant treatments: electro convulsive therapy (ECT), sleep deprivation (SD), and fluoxetine (FLX), the most commonly used slow-onset antidepressant. Each of these antidepressant treatments was applied with the same regimen known to have clinical efficacy: 2 days of ECT (four sessions per day), 24 h of SD, and 14 days of daily treatment of FLX, respectively. Transcriptional changes were evaluated on RNA extracted from seven different brain regions using the Affymetrix rat genome microarray 230 2.0. The gene chip data were validated using in situ hybridization or autoradiography for selected genes. The major findings of the study are: 1. The transcriptional changes induced by SD, ECT and SSRI display a regionally specific distribution distinct to each treatment. 2. The fast-onset, short-lived antidepressant treatments ECT and SD evoked transcriptional changes primarily in the catecholaminergic system, whereas the slow-onset antidepressant FLX treatment evoked transcriptional changes in the serotonergic system. 3. ECT and SD affect in a similar manner the same brain regions, primarily the locus coeruleus, whereas the effects of FLX were primarily in the dorsal raphe and hypothalamus, suggesting that both different regions and pathways account for fast onset but short lasting effects as compared to slow-onset but long-lasting effects. However, the similarity between effects of ECT and SD is somewhat confounded by the fact that the two treatments appear to regulate a number of transcripts in an opposite manner. 4. Multiple transcripts (e.g. brain-derived neurotrophic factor (BDNF), serum/glucocorticoid-regulated kinase (Sgk1)), whose level was reported to be affected by antidepressants or behavioral manipulations, were also found to be regulated by the treatments used in the present study. Several novel findings of transcriptional regulation upon one, two or all three treatments were made, for the latter we highlight homer, erg2, HSP27, the proto oncogene ret, sulfotransferase family 1A (Sult1a1), glycerol 3-phosphate dehydrogenase (GPD3), the orphan receptor G protein-coupled receptor 88 (GPR88) and a large number of expressed sequence tags (ESTs). 5. Transcripts encoding proteins involved in synaptic plasticity in the hippocampus were strongly affected by ECT and SD, but not by FLX. The novel transcripts, concomitantly regulated by several antidepressant treatments, may represent novel targets for fast onset, long-duration antidepressants.