Non-competitive Receptor Antagonist Research Articles

Bioequivalence of Two Perampanel 12mg Tablets in Healthy, Adult, Human Subjects under Fed Conditions - An Open Label, Cross Over Study

Background: Perampanel is a glutamate non-competitive receptor antagonist that is effective as adjunctive therapy for epilepsy. The main objective of the present research is to compare the bioavailability and to evaluate the bioequivalence between the test and reference product. The secondary objective is to assess the safety and tolerability of the drug

Immunomodulatory IL-23 receptor antagonist peptide nanocoatings for implant soft tissue healing.

Peri-implantitis, caused by an inflammatory response to pathogens, is the leading cause of dental implant failure. Poor soft tissue healing surrounding implants - caused by inadequate surface properties - leads to infection, inflammation, and dysregulated keratinocyte and macrophage function. One activated inflammatory response, active around peri-implantitis compared to healthy sites, is the IL-23/IL-17A cytokine axis. Implant surfaces can be synthesized with peptide nanocoatings to present immunomodulatory motifs to target peri-implant keratinocytes to control macrophage polarization and regulate inflammatory axises toward enhancing soft tissue healing. We synthesized an IL-23 receptor (IL-23R) noncompetitive antagonist peptide nanocoating using silanization and evaluated keratinocyte secretome changes and macrophage polarization (M1-like "pro-inflammatory" vs. M2-like "pro-regenerative"). IL-23R antagonist peptide nanocoatings were successfully synthesized on titanium, to model dental implant surfaces, and compared to nonfunctional nanocoatings and non-coated titanium. IL-23R antagonist nanocoatings significantly decreased keratinocyte IL-23, and downstream IL-17A, expression compared to controls. This peptide noncompetitive antagonistic function was demonstrated under lipopolysaccharide stimulation. Large scale changes in keratinocyte secretome content, toward a pro-regenerative milieu, were observed from keratinocytes cultured on the IL-23R antagonist nanocoatings compared to controls. Conditioned medium collected from keratinocytes cultured on the IL-23R antagonist nanocoatings polarized macrophages toward a M2-like phenotype, based on increased CD163 and CD206 expression and reduced iNOS expression, compared to controls. Our results support development of IL-23R noncompetitive antagonist nanocoatings to reduce the pro-inflammatory IL-23/17A pathway and augment macrophage polarization toward a pro-regenerative phenotype. Immunomodulatory implant surface engineering may promote soft tissue healing and thereby reduce rates of peri-implantitis.

Oligomeric Aβ25–35 induces the tyrosine phosphorylation of PSD-95 by SrcPTKs in rat hippocampal CA1 subfield

Purpose: Although amyloid-β (Aβ) is one of the neuropathological hallmarks of Alzheimer’s Disease (AD), the mechanisms of Aβ neurotoxicity remain to be clarified. This study was aimed to evaluate the effect of Aβ on postsynaptic density-95 (PSD-95) tyrosine phosphorylation. Elucidating the regulatory mechanisms underlying it may be a promising therapy in AD. Methods: Aβ25–35 oligomers (20 μg/rat) were administered intracerebroventricularly in adult male Sprague-Dawley rats. PSD-95 tyrosine phosphorylation was assessed using immunoprecipitation followed by immunoblot analysis. Immunoblot was applied for measuring the protein levels of PSD-95 and β-actin. Results: Following 3, 7, 14, 21 days after oligomeric Aβ25–35 treatment, the tyrosine phosphorylation of PSD-95 increased significantly, and peaked at 3 days after oligomeric Aβ25–35 treatment in hippocampal CA1 subfield. Src family protein tyrosine kinases (SrcPTKs) specific inhibitor PP2 attenuated the tyrosine phosphorylation of PSD-95 induced by Aβ–35. Amantadine [N-methyl-D-aspartate (NMDA) receptor noncompetitive antagonist], NVP-AAM077 (GluN2A-containing NMDA receptor selective inhibitor) and Ro25-6981 (GluN2B-containing NMDA receptor selective inhibitor) also suppressed the Aβ25–35-induced PSD-95 tyrosine phosphorylation. Conclusion: These results suggest that Aβ oligomers induce the tyrosine phosphorylation of PSD-95 by SrcPTKs, which is mediated by the activation of GluN2A- and GluN2B-containing NMDA receptors. Section: Disease-Related Neuroscience

Pharmacological and non pharmacological treatment of Alzheimer's disease

To date, only symptomatic treatments exist for Alzheimer’s disease. Pharmacological treatment aims to counterbalance the neurotransmitter disturbance. Three cholinesterase inhibitors (CIs) are currently available and have been approved for the treatment of mild to moderate AD. A further therapeutic option available is memantine, an N-methyl- D-aspartate receptor noncompetitive antagonist. Other symptomatic treatments can be used for the behavioral and psychiatric symptoms of the disease. Non-drug interventions include things like memory training, mental and social stimulation, and physical exercise programs. Some of these strategies could possibly improve people’s cognitive performance and increase their independence. Treatments capable of stopping or at least effectively modifying the course of AD, referred to as ‘disease-modifying’ drugs, are still under extensive research. To block the progression of the disease they have to interfere with the pathogenic steps responsible for the clinical symptoms, including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation, inflammation, oxidative damage, iron deregulation and cholesterol metabolism.

Short peptide with an inhibitory activity on the NMDA/Gly-induced currents

ABSTRACTN-methyl-D-aspartate (NMDA) receptors are considered to be one of the most promising targets for treatment-resistant depression. The majority of known ligands may cause undesirable side-effects, except tetrapeptide rapastinel which demonstrated rapid antidepressant effect without psychotomimetic side effects. High shape similarity was noticed between dipeptide Phe-Tyr and NMDA receptor non-competitive antagonist ifenprodil which imply the possibility for antagonistic action of this peptide. A series of analogs were selected based on the docking results and molecular dynamics simulations. A dipeptide D-Phe-L-Tyr showed modest inhibitory activity comparable to rapastinel.

Computational Characterization of the Binding of Non-Competitive Inhibitors to AMPA Receptors

Non-competitive inhibitors of AMPA receptors have attracted significant interest in the recent years as potential antiepileptic drugs. While a considerable number of small molecules have been identified and tested as AMPA receptor non-competitive antagonists, only pyridone perampanel (PMP) has been approved for clinical use as an antiepileptic drug. PMP, however, still causes side effects at higher doses, indicating the need for safer and more effective drugs. Recently resolved crystal structures of AMPA receptor complexes of GYKI 53655 (GYKI), CP 465022 (CP), and PMP provided new structural information on non-competitive inhibitor binding to AMPA receptors. While these structurally dissimilar inhibitors share a common binding site, each ligand interacts differently with individual amino acid residues in the binding pocket. However, due to the limited resolution of the crystal structures they do not provide a comprehensive atomistic picture of specific protein-ligand interactions that are important in inhibitor binding. In this study, molecular docking along with molecular dynamics (MD) simulations and binding energy calculations were carried out to assess the stability of crystallographically determined binding modes and explore potential alternative binding modes of inhibitors GYKI, CP, and PMP. Our MD simulation results provide structural insights into interactions of these inhibitors with AMPA receptors and highlight the features of the AMPA receptor non-competitive inhibitor binding pocket that are important in accommodating structurally different inhibitors. This information will aid in structure-based design of new non-competitive inhibitors that target AMPA receptors.

Maternal Overnutrition Induces Long-Term Cognitive Deficits across Several Generations

Ample evidence from epidemiological studies has linked maternal obesity with metabolic disorders such as obesity, cardiovascular disease, and diabetes in the next generation. Recently, it was also shown that maternal obesity has long-term effects on the progeny’s central nervous system. However, very little is known regarding how maternal overnutrition may affect, in particular, the cognitive abilities of the offspring. We reported that first-generation offspring exposed to a maternal high-fat diet (MHFD) displayed age-dependent cognitive deficits. These deficits were associated with attenuations of amino acid levels in the medial prefrontal cortex and the hippocampus regions of MHFD offspring. Here, we tested the hypothesis that MHFD in mice may induce long-term cognitive impairments and neurochemical dysfunctions in the second and third generations. We found that MHFD led to cognitive disabilities and an altered response to a noncompetitive receptor antagonist of the N-Methyl-D-aspartic acid (NMDA) receptor in adult MHFD offspring in both second and third generations in a sex-specific manner. Our results suggest that maternal overnutrition leads to an increased risk of developing obesity in subsequent generations as well as to cognitive impairments, affecting learning and memory processes in adulthood. Furthermore, MHFD exposure may facilitate pathological brain aging which is not a consequence of obesity. Our findings shed light on the long-term effects of maternal overnutrition on the development of the central nervous system and the underlying mechanisms which these traits relate to disease predisposition.

Accumbens brain-derived neurotrophic factor (BDNF) transmission inhibits cocaine seeking.

Brain-derived neurotrophic factor (BDNF) regulates a variety of physiological processes, and several studies have explored the role of BDNF in addiction-related brain regions like the nucleus accumbens core (NAcore). We sought to understand the rapid effects of endogenous BDNF on cocaine seeking. Rats were trained to self-administer cocaine and extinguished. We then microinjected two inhibitors of BDNF stimulation of tropomyosin receptor kinase B (TrkB), the non-competitive receptor antagonist ANA-12 and TrkB/Fc, a fusion protein that binds BDNF and prevents TrkB stimulation. Blocking TrkB or inactivating BDNF in NAcore potentiated active lever pressing, showing that endogenous BDNF tone was present and supplying inhibitory tone on cue-induced reinstatement. To determine if exogenous BDNF also negatively regulated reinstatement, BDNF was microinjected into NAcore 15minutes before cue-induced reinstatement. BDNF decreased cocaine seeking through TrkB receptor binding, but had no effect on inactive lever pressing, spontaneous or cocaine-induced locomotion, or on reinstated sucrose seeking. BDNF-infusion potentiated within trial extinction when microinjected in the NAcore during cue- and context+cue induced reinstatement, and the inhibition of lever pressing lasted at least 3days post injection. Although decreased reinstatement endured for 3days when BDNF was administered prior to a reinstatement session, when microinjected before an extinction session or in the home cage, BDNF did not alter subsequent cued-reinstatement. Together, these data show that endogenous BDNF acts on TrKB to provide inhibitory tone on reinstated cocaine seeking, and this effect was recapitulated by exogenous BDNF.

Discovery of a Novel Series of Orally Bioavailable and CNS Penetrant Glucagon-like Peptide-1 Receptor (GLP-1R) Noncompetitive Antagonists Based on a 1,3-Disubstituted-7-aryl-5,5-bis(trifluoromethyl)-5,8-dihydropyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione Core.

A duplexed, functional multiaddition high throughput screen and subsequent optimization effort identified the first orally bioavailable and CNS penetrant glucagon-like peptide-1 receptor (GLP-1R) noncompetitive antagonist. Antagonist 5d not only blocked exendin-4-stimulated insulin release in islets but also lowered insulin levels while increasing blood glucose in vivo.

Comparative Bioavailability of Two Oral Perampanel Formulations in Healthy Subjects: A Randomized, Open Label, Single-Dose, 2-Way Crossover Study

Background: Perampanel is a glutamate non-competitive receptor antagonist that is effective as adjunctive treatment for epilepsy. No studies regarding comparative bioavailability between a generic perampanel formulation and the brand-name product have been published in the literature. Therefore, the goal of the present investigation was to compare the bioavailability and to evaluate the bioequivalence between a novel pharmaceutical equivalent 12 mg film-coated tablet formulation and the reference product. Methods: An open label, randomized-sequence, two-period, two-treatment, single-dose, crossover design study in healthy volunteers(n=24) was conducted. The treatment was split out by a 42 days wash-out period. The informed consent was signed by all volunteers. Healthy subjects of both genders, including non-pregnant and nonlactating females between 21-55 years with Quetelet index between 19-29 kg/m2 were enrolled. Blood samples were withdrawn in vacutainers with EDTA over 168 h and plasma levels of perampanel were measured by HPLC/ fluorescence method. Pharmacokinetic (PK) variables (Cmax, AUC0-last, and AUCinf) after a single oral administration dose of the test and reference treatments were analyzed by a non-compartmental PK model using natural logtransformed data and were compared by ANOVA for a two-treatment crossover design. Bioequivalence between the two formulations was evaluated using the 90% Confidence Interval (CI) comprised between 80-125% corresponding to the ratio of the geometric means for log-transformed PK parameters. Results: A similar bioavailability between products was determined. Test and reference formulations showed no statistically significant differences in relation to the fixed effect of period, sequence, treatment and volunteers within sequence as random effect for PK variables. The estimated point and 90% CI of the ratios of Cmax, AUC0-last and AUCinf were 0.92 (0.83-1.03), 1.04(0.98-1.10) and 0.98 (0.86-1.11), respectively. The formulations showed comparable safety and tolerability. Conclusion: The new pharmaceutical equivalent perampanel 12 mg film-coated tablet formulation was also bioequivalent to the reference product. Therefore, both drugs are interchangeable.

Evaluating the efficacy of memantine on improving cognitive functions in epileptic patients receiving anti-epileptic drugs: A double-blind placebo-controlled clinical trial (Phase IIIb pilot study).

Objectives:People with epilepsy have greater cognitive and behavioral dysfunction than the general population. There is no specific treatment available for cognitive impairment of these patients. We aimed to evaluate the effects of memantine, an N-methyl-D-aspartate-type glutamate receptor noncompetitive antagonist, on improving cognition and memory functions in epileptic patients with cognitive and memory impairment, who received anti-epileptic drugs (AEDs).Methods:We did a randomized, double-blind, placebo-controlled parallel group trial, in SRM Medical College Hospital and Research Centre, Kattankulathur, Kancheepuram, Tamil Nadu, India between April 2013 and September 2013. Fifty-nine epileptic patients taking AEDs with subjective memory complaints were recruited and randomized to either Group 1 to receive 16 weeks of once-daily memantine, (5 mg for first 8 weeks, followed by memantine 10 mg for next 8 weeks) or Group 2 to receive once daily placebo. This trial is registered with Clinical Trial Registry of India CTRI/2013/04/003573.Results:Of 59 randomized patients, 55 patients completed the study (26 memantine and 29 placebo). Memantine group showed statistically significant improvement in total mini mental state examination score from baseline (P = 0.765) to 16th week (P < 0.001) in comparison with the placebo. The Weshler's Memory Scale total score in memantine group improved significantly after 8 weeks (P = 0.002) compared with baseline (P = 0.873) and highly significant at the end of 16th week (P < 0.001). The self-rated quality of life and memory in memantine group also significantly improved at the study end.Conclusion:We conclude that once-daily memantine (10 mg) treatment significantly improved cognition, memory and quality of life in epileptic patients with mild to moderate cognitive impairment and was found to have a favorable safety profile.

Prolonged reversal of the phencyclidine-induced impairment in novel object recognition by a serotonin (5-HT)1A-dependent mechanism

Many acute treatments transiently reverse the deficit in novel object recognition (NOR) produced by subchronic treatment with the N-methyl-d-aspartate receptor non-competitive antagonist, phencyclidine (PCP), in rodents. Treatments which restore NOR for prolonged periods after subchronic PCP treatment may have greater relevance for treating the cognitive impairment in schizophrenia than those which restore NOR transiently. We examined the ability of post-PCP subchronic lurasidone, an atypical APD with potent serotonin (5-HT)1A partial agonism and subchronic tandospirone, a selective 5-HT1A partial agonist, to enable prolonged reversal of the subchronic PCP-induced NOR deficit. Rats treated with subchronic PCP (2mg/kg, twice daily for 7 days) or vehicle, followed by a 7day washout period were subsequently administered lurasidone or tandospirone twice daily for 7 days (day 15–21), and tested for NOR weekly for up to two additional weeks. Subchronic lurasidone (1, but not 0.1mg/kg) or tandospirone (5, but not 0.6mg/kg) significantly reversed the PCP-induced NOR deficit at 24h and 7days after the last injection, respectively. The effect of lurasidone persisted for one more week (day 36, 14 days after the last lurasidone dose), while tandospirone-treated rats were able to perform NOR at 7, but not 14, days after the last tandospirone dose. Co-administration of WAY100635 (0.6mg/kg), a 5-HT1A antagonist, with lurasidone, blocked the ability of lurasidone to restore NOR, suggesting that 5-HT1A receptor stimulation is necessary for lurasidone to reverse the effects of PCP. The role of dopamine, GABA and the MAPK/ERK signalling pathway in the persistent, but not indefinite, restoration of NOR is discussed.

Feasibility of using memantine in smoking cessation among cancer survivors.

1559 Background: Memantine, an N-methyl-D-aspartate receptor noncompetitive antagonist, has been proposed for smoking cessation by virtue of opposing the effects of glutamate in the CNS “addiction ...

Cure for Alzheimer’s Disease

Alzheimer’s disease (AD) is progressively being recognized amongst the most vital medical and social issues in older individuals in industrialized and non-industrialized countries. To date, just symptomatic medications exist for this disease, all attempting to offset the neurotransmitter disturbance. Recently, cholinesterase inhibitors (CIs) are now accessible and have been authorized for the treatment of mild to moderate AD. Further remedial alternative available for moderate to severe AD is memantine, an N-methyl-D-aspartate receptor noncompetitive antagonist. Treatments equipped for halting or slightly adjusting the course of AD are known as “ailment changing” medications, and are still under extensive examination. To obstruct the movement of the ailment, they need to interfere with the pathogenic steps in charge of the clinical symptoms, including the disposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation, irritation, oxidative damage, iron deregulation and cholesterol metabolism. This paper discusses the cure for Alzheimer’s disease, the current symptomatic treatments and the treatment of mild and moderate Alzheimer’s disease and the functions of its drugs.

Combination Therapy of Anti-Tau and Anti-Amyloid Drugs for Disease Modification in Early-stage Alzheimer's Disease: Socio-economic Considerations Modeled on Treatments for Tuberculosis, HIV/AIDS and Breast Cancer.

Current drugs for treatment of mild to severe dementia of the Alzheimer's type include cholinesterase inhibitors and the NMDA non-competitive receptor antagonist memantine. There is controversy as to the additive benefit of these symptomatic drugs, and their effects are clinically modest. Patients with Alzheimer's disease (AD) are known to have characteristic pathology, including senile plaques with amyloid beta-protein aggregates and neurofibrillary tangles with assembled tau proteins, which start in the hippocampus and spread to neighboring areas. Amyloid and tau modifying drugs are under clinical testing. Based on this pathophysiology, it is crucial to investigate whether anti-amyloid and anti-tau combined therapy would show efficacy in early stage of AD, beyond what could be achieved with anti-amyloid or anti-tau monotherapy. It is equally important to consider the socio-economic implications of such a combination therapy, if effective. We hypothesize that the high costs of combination therapy for early-stage AD patients will require societal and public health initiatives to ensure universal access to AD treatment. In order to better predict these socio-economic implications, we summarize the management of other combination therapies used for tuberculosis, HIV/AIDS, and breast cancer, based on a database search of PubMed and other relevant sources. We put forward a framework for testing a potential anti-amyloid and anti-tau disease modifying combination therapy for early-stage AD patients and present an analysis of the socio-economic implications of such a combination therapy.

The Novel Object Recognition Test in Rodents in Relation to Cognitive Impairment in Schizophrenia

Novel object recognition (NOR) in rodents is analogous in some ways to human declarative (episodic) memory, one of the seven cognitive domains which are abnormal in schizophrenia. Cognitive impairment in schizophrenia (CIS) accounts for the largest proportion of the poor functional outcomes in this complex syndrome, with psychosis and negative symptoms accounting for much of the rest. Current atypical antipsychotic drugs (APDs) e.g. amisulpride, aripiprazole, clozapine, lurasidone, olanzapine and risperidone, and typical APDs as well, significantly improve some, but not all aspects of CIS, including declarative memory, but not in all patients, and rarely restore normal function. Thus, finding new ways to prevent or treat CIS is a major goal of current schizophrenia research, with animal models as an essential tool. NOR in rodents is valuable in this regard because of its relationship to declarative memory, the extensive knowledge of its underlying circuitry, and the ease and reliability of assessment. Sub-chronic administration of an N-methyl-Daspartate receptor (NMDAR) non-competitive antagonist, e.g. phencyclidine (PCP), dizocilpine (MK-801) or ketamine, is a favored means to study NOR as a model of CIS, because it produces deficient glutamatergic and GABAergic function, both of which have been implicated in the development of CIS. Transgenic mice and anti-cholinergic-induced deficits in NOR have received less attention. We review here NOR studies in rodents that bear upon CIS, including the evidence that atypical, but not typical APDs, as well as specific ligands, e.g. 5-HT1A partial agonists, 5-HT7 antagonists, D1 agonists, among others, can restore NOR following sub-chronic NMDAR antagonist treatment, and can also prevent the impairment in NOR produced by sub-chronic NMDAR antagonists. We discuss how well these findings translate to the bedside.

Evaluation of medication treatment for Alzheimer's disease on clinical evidence

Objective To formulate the best treatment plan for Alzheimer's disease patients by evaluating the therapeutic efficacy and side effect of various evidence-based programs. Methods Alzheimer's disease, donepezil, rivastigmine, galantamine, memantine, rosiglitazone, etc. were defined as retrieval words. PubMed, Cochrane Library, Wanfang Data and China National Knowledge Infrastructure (CNKI) databases were used with applying of manual searching. Systematic reviews, randomized controlled trials (RCT), controlled clinical trials and case-observation studies were collected and evaluated by Jadad Scale. Results After screening, 33 selected resources included 14 systematic reviews, 14 randomized controlled trials, 4 controlled clinical trials and 1 case-observation study. According to Jadad Scale, total 28 articles were evaluated to be high quality (12 with score 4, 10 score 5, 6 score 7), and 5 were low quality with score 3. It was summarized as follows: 1) Alzheimer's disease is a progressive neurodegenerative disease for which no cure exists. To date, only symptomatic treatments with cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and an N-methyl-D-aspartate (NMDA) receptor noncompetitive antagonist (memantine), are effective and well tolerated to counterbalance the neurotransmitter disturbance, but cannot limit or impact on disease progression. 2) Disease modifying drug is an potential agent, with persistent effect on slowing the progression of structural damage, and can be detected even after withdrawing the treatment. Many types of disease modifying drugs are undergoing clinical trials. Conclusions Using evidence-based medicine methods can provide best clinical evidence on Alzheimer's disease treatment. doi: 10.3969/j.issn.1672-6731.2014.03.009

Current and future treatments for Alzheimer's disease.

Alzheimer's dementia (AD) is increasingly being recognized as one of the most important medical and social problems in older people in industrialized and non-industrialized nations. To date, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance. Three cholinesterase inhibitors (CIs) are currently available and have been approved for the treatment of mild to moderate AD. A further therapeutic option available for moderate to severe AD is memantine, an N-methyl-D-aspartate receptor noncompetitive antagonist. Treatments capable of stopping or at least effectively modifying the course of AD, referred to as 'disease-modifying' drugs, are still under extensive research. To block the progression of the disease they have to interfere with the pathogenic steps responsible for the clinical symptoms, including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation, inflammation, oxidative damage, iron deregulation and cholesterol metabolism. In this review we discuss current symptomatic treatments and new potential disease-modifying therapies for AD that are currently being studied in phase I-III trials.

D1 receptor agonists reverse the subchronic phencyclidine (PCP)-induced novel object recognition (NOR) deficit in female rats

Development of dopamine (DA) D1 receptor agonists is a priority to improve cognitive impairment in schizophrenia (CIS). This study examined the dose–response relationship of the selective D1 agonist, SKF38393 (0.5–40mg/kg), to reverse the deficit in novel object recognition (NOR), an analog of declarative memory in man, produced by subchronic phencyclidine (PCP), an N-methyl-d-aspartate (NMDA) receptor non-competitive antagonist, and the ability of the D1 antagonists, SCH23390 (0.05mg/kg) and SKF83566 (0.15mg/kg), to impair NOR in normal Long-Evans female rats. We also examined the ability of tandospirone, a serotonin (5-HT)1A receptor partial agonist, and LY341495, a mGluR2/3 receptor antagonist, to potentiate or block the effects of SKF38393 on NOR, respectively. SKF38393 reversed the persistent NOR deficit produced by subchronic PCP; the dose–response curve for SKF38393 was an inverted U-shape, with the peak effect at 6mg/kg. SKF83566 and SCH23390 impaired NOR in normal rats. Co-administration of sub-effective doses of SKF38393 (0.25mg/kg) and tandospirone (0.2mg/kg) improved the PCP-induced NOR deficit, while LY341495 (1mg/kg) blocked the ameliorating effect of SKF38393 (6mg/kg), respectively. These data provide the first evidence that the reversal of the PCP-induced NOR deficit by D1 agonism has an inverted U-shaped dose–response curve and that 5-HT1A and mGluR2/3 receptor signalling facilitates the efficacy of D1 agonism to improve these deficits. These data suggest that although D1 agonists may be useful to improve CIS, these agents, particularly higher doses, may also worsen cognitive function in some patients, because of an inverted U-shaped dose response curve.

The pharmacological profile of ELIC, a prokaryotic GABA-gated receptor

The Erwinia ligand-gated ion channel (ELIC) is a bacterial homologue of vertebrate Cys-loop ligand-gated ion channels. It is activated by GABA, and this property, combined with its structural similarity to GABAA and other Cys-loop receptors, makes it potentially an excellent model to probe their structure and function. Here we characterise the pharmacological profile of ELIC, examining the effects of compounds that could activate or inhibit the receptor. We confirm that a range of amino acids and classic GABAA receptor agonists do not elicit responses in ELIC, and we show the receptor can be at least partially activated by 5-aminovaleric acid and γ-hydroxybutyric acid, which are weak agonists. A range of GABAA receptor non-competitive antagonists inhibit GABA-elicited ELIC responses including α-endosulfan (IC50 = 17 μM), dieldrin (IC50 = 66 μM), and picrotoxinin (IC50 = 96 μM) which were the most potent. Docking suggested possible interactions at the 2′ and 6′ pore-lining residues, and mutagenesis of these residues supports this hypothesis for α-endosulfan. A selection of compounds that act at Cys-loop and other receptors also showed some efficacy at blocking ELIC responses, but most were of low potency (IC50 > 100 μM). Overall our data show that a number of compounds can inhibit ELIC, but it has limited pharmacological similarity to GLIC and to Cys-loop receptors.