Weak Antagonist Research Articles

DRUG REPOSITIONING: Revisiting the basic psychopharmacological mechanism of action for agomelatine and where it should be classified?

Concerning Agomelatine, as of this present moment and deeply analyzing things from the psychopharmacological point of view, the utmost important question yet to be answered is “why should the drug Agomelatine be regarded as an antidepressant agent when it did not actually possess the necessary pharmacoactivities and mechanism of actions that adequately qualified it to be classified under the family of antidepressants as done in previously published reference literatures?” The mystery, approach, and rationale behind this act of classification phenomenon were actually and inevitably putting a square peg inside a round hole, which is scientifically deemed unfit and inappropriate. This act of classification phenomenon makes Agomelatine to be referred to as a paradoxical agent that contradicts itself. Agomelatine is a melatonergic MT1 and MT2 receptors agonist and a selective serotonergic 5-HT2B and 5-HT2C receptors antagonist (MASSA). The 5-HT2B receptors are poorly represented in the central nervous system (CNS) in contrast to the 5-HT2C receptors. Its prochronobiological activity resynchronizes circadian rhythms in experimental animal models of delayed sleep phase syndrome via its melatonergic MT1 and MT2 receptors agonistic effect. By antagonizing 5-HT2C receptors, Agomelatine disinhibits/increases norepinephrine and dopamine release specifically in the neocortical areas such as the prefrontal cortex but neither in the subcortical areas such as the striatum nor nucleus accumbens; therefore, it is sometimes referred to as a norepinephrine–dopamine disinhibitor (NDD). Furthermore, by antagonizing 5-HT2C receptors in the subcortical areas such as basal ganglia, mesolimbic cortex and hippocampus; Agomelatine produces anxiolytic effect clinically. Because Agomelatine lacks inhibitory pharmacoactivity at the monoaminergic reuptake transporter pumps (SERT, NET, and DAT), does not inhibit the enzyme monoamine oxidase, has neither weak antagonist nor partial agonist activity at the dopaminergic D2 receptor, and also lacks antagonistic activity at both the noradrenergic α2-receptor and N- methyl-D-aspartic acid (NMDA)-glutamatergic ionoceptor, it should not be regarded and accepted as an antidepressant but rather it should be classified as an anxiolytic sedative agent on account of its melatonergic MT1 and MT2 receptors agonist and selective serotonergic 5-HT2C receptor antagonistic (MASSA) properties.

Exploring Environmental Chemicals and Risk of Breast Cancer during the Menopausal Transition

Teasing out the biologic mechanisms of endocrine-disrupting chemicals (EDCs) in epidemiologic studies is complicated given their heterogeneity, and assessing the effects of exposures in vitro assays and in vivo animal studies may not reflect what happens in human populations. Therefore, using a transdisciplinary approach with a population-based epidemiologic study, in vitro assays, and in vivo mouse models, offers a targeted opportunity to evaluate the role of EDCs in promoting breast cancer during the menopausal transition. We are specifically investigating the effects of three polybrominated diphenyl ethers (BDE-47, BDE-100, and BDE-153). Using blood samples collected during the menopausal transition from women in the prospective California Teachers Study (CTS) cohort, we are assessing the effects of PBDE levels on the epigenome through miRNA and global and gene methylation assays, on total estrogenic activity, and on risk of developing breast cancer. In in vitro experiments in breast cell lines, we are measuring the effects of PBDEs at a range of levels, including at the CTS serum levels, to assess their effects on the activity of the estrogen and progesterone receptors and aromatase, as well as on the epigenome, transcriptome, and cell proliferation. Initial results suggest that BDE-47 acts as a mild ER-α agonist and BDE-100 and BDE-153 act as weak antagonists. In in vivo mouse models, we are testing whether combined effects of PBDEs at the levels seen in serum of the CTS samples cause mammary gland lesions. We first are studying ovariectomized mice, which have minimal estrogenic activity in their bodies, and then will use an ovarian-failure mouse model to represent the menopausal transition. Definitive changes in uterus weight and gene expression profiles have been observed in mice following 1-week feeding of PBDE-containing diet.

4-Aminophenyl acetamides and propanamides as potent transient receptor potential vanilloid 1 (TRPV1) ligands

A series of 2-(3,5-substituted 4-aminophenyl)acetamide and propanamide derivatives were investigated as human TRPV1 antagonists. The analysis of the structure-activity relationship indicated that 2-(3,5-dihalo 4-aminophenyl)acetamide analogues displayed excellent antagonism of hTRPV1 activation by capsaicin and showed improved potency compared to the corresponding propanamides. The most potent antagonist (36) exhibited potent and selective antagonism for hTRPV1 not only to capsaicin but also to NADA and elevated temperature; however, it only displayed weak antagonism to low pH. Further studies indicated that oral administration of antagonist 36 blocked the hypothermic effect of capsaicin in vivo but demonstrated hyperthermia at that dose. A docking study of 36 was performed in our established hTRPV1 homology model to understand its binding interactions with the receptor and to compare with that of previous antagonist 1.

Molecular targets of atypical antipsychotics: From mechanism of action to clinical differences.

The introduction of atypical antipsychotics (AAPs) since the discovery of its prototypical drug clozapine has been a revolutionary pharmacological step for treating psychotic patients as these allow a significant recovery not only in terms of hospitalization and reduction in symptoms severity, but also in terms of safety, socialization and better rehabilitation in the society. Regarding the mechanism of action, AAPs are weak D2 receptor antagonists and they act beyond D2 antagonism, involving other receptor targets which regulate dopamine and other neurotransmitters. Consequently, AAPs present a significant reduction of deleterious side effects like parkinsonism, hyperprolactinemia, apathy and anhedonia, which are all linked to the strong blockade of D2 receptors. This review revisits previous and current findings within the class of AAPs and highlights the differences in terms of receptor properties and clinical activities among them. Furthermore, we propose a continuum spectrum of "atypia" that begins with risperidone (the least atypical) to clozapine (the most atypical), while all the other AAPs fall within the extremes of this spectrum. Clozapine is still considered the gold standard in refractory schizophrenia and in psychoses present in Parkinson's disease, though it has been associated with adverse effects like agranulocytosis (0.7%) and weight gain, pushing the scientific community to find new drugs as effective as clozapine, but devoid of its side effects. To achieve this, it is therefore imperative to characterize and compare in depth the very complex molecular profile of AAPs. We also introduce relatively new concepts like biased agonism, receptor dimerization and neurogenesis to identify better the old and new hallmarks of "atypia". Finally, a detailed confrontation of clinical differences among the AAPs is presented, especially in relation to their molecular targets, and new means like therapeutic drug monitoring are also proposed to improve the effectiveness of AAPs in clinical practice.

Bargaining in asymmetric crisis

Diplomacy, defined as formal communication and bargaining between states, is subject to limits that diplomatic theory must demarcate and understand. This article compares state incentives and disincentives (including rejection of negotiation as well as refusal to concede) affecting the decision whether to negotiate in six cases of interstate crisis between militarily unequal antagonists. While it has been argued that asymmetric powers are more likely to reach negotiating agreement than their symmetric counterparts, with weaker states doing surprisingly well, that finding is questioned here in the crisis context. For example, the militarily inferior antagonist, attracted to diplomacy as an alternative to war, might well anticipate inferior results from direct negotiations. The weaker antagonist’s unwillingness in these cases to negotiate with a strong opponent suppressed diplomacy, but great power support for the weaker side, and the stronger power’s lack of war readiness, added to the stronger antagonist’s willingness to negotiate.

Synthesis and activity of di- or trisubstituted N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives on the central nervous system

Aim of the study was evaluation of anxiolytic, antidepressant, anticonvulsant and analgesic activity in a series of a consistent group of compounds. A series of eleven new N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives has been obtained. Their affinity towards 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, D2 and α1 receptors has been assessed, and then functional assays were performed. The compounds were evaluated in mice, i.p. for their antidepressant-like (forced swim test), locomotor, anxiolytic-like (four-plate test) activities as well as – at higher doses – for anticonvulsant potential (MES) and neurotoxicity (rotarod). Two compounds (3, 6) were also evaluated for their analgesic activity in neuropathic pain models (streptozocin test, oxaliplatin test) and they were found active against allodynia in diabetic neuropathic pain at 30 mg/kg. Among the compounds, anxiolytic-like, anticonvulsant or analgesic activity was observed but antidepressant-like activity was not. One of the two most interesting compounds is 1-{2-[2-(2,4,6-trimethylphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazine dihydrochloride (9), exhibiting anxiolytic and anticonvulsant activity in mice, i.p. 30 min after administration (at 2.5 mg/kg and ED50 = 26.33 mg/kg, respectively), which can be justified by the receptor profile: 5-HT1A Ki = 5 nM (antagonist), 5-HT7 Ki = 70 nM, α1 Ki = 15 nM, D2 Ki = 189 nM (antagonist). Another interesting compound is 1-[3-(2,4,6-trimethylphenoxy)propyl]-4-(4-methoxyphenyl)piperazine dihydrochloride (3), exhibiting anxiolytic, anticonvulsant and antiallodynic activity in mice, i.p., 30 min after administration (at 10 mg/kg, ED50 = 23.50 mg/kg, at 30 mg/kg, respectively), which can be related with 5-HT1A weak antagonism (Ki = 146 nM), or other possible mechanism of action, not evaluated within presented study. Additionally, for the most active compound in the four-plate test (7), molecular modeling was performed (docking to receptors 5-HT1A, 5-HT2A, 5-HT7, D2 and α1A).

Antagonism of the Protein Kinase R Pathway in Human Cells by Rhesus Cytomegalovirus.

While cytomegalovirus (CMV) infections are often limited in host range by lengthy coevolution with a single host species, a few CMVs are known to deviate from this rule. For example, rhesus macaque CMV (RhCMV), a model for human CMV (HCMV) pathogenesis and vaccine development, can replicate in human cells, as well as in rhesus cells. Both HCMV and RhCMV encode species-specific antagonists of the broadly acting host cell restriction factor protein kinase R (PKR). Although the RhCMV antagonist of PKR, rTRS1, has very limited activity against human PKR, here, we show it is essential for RhCMV replication in human cells because it prevents human PKR from phosphorylating the translation initiation factor eIF2α, thereby allowing continued translation and viral replication. Although rTRS1 is necessary for RhCMV replication, it is not sufficient to rescue replication of HCMV lacking its own PKR antagonists in human fibroblasts. However, overexpression of rTRS1 in human fibroblasts enabled HCMV expressing rTRS1 to replicate, indicating that elevated levels or early expression of a weak antagonist can counteract a resistant restriction factor like human PKR. Exploring potential mechanisms that might allow RhCMV to replicate in human cells revealed that RhCMV makes no less double-stranded RNA than HCMV. Rather, in human cells, RhCMV expresses rTRS1 at levels 2 to 3 times higher than those of the HCMV-encoded PKR antagonists during HCMV infection. These data suggest that even a modest increase in expression of this weak PKR antagonist is sufficient to enable RhCMV replication in human cells.IMPORTANCE Rhesus macaque cytomegalovirus (RhCMV) offers a valuable model for studying congenital human cytomegalovirus (HCMV) pathogenesis and vaccine development. Therefore, it is critical to understand variations in how each virus infects and affects its host species to be able to apply insights gained from the RhCMV model to HCMV. While HCMV is capable only of infecting cells from humans and very closely related species, RhCMV displays a wider host range, including human as well as rhesus cells. RhCMV expresses an antagonist of a broadly acting antiviral factor present in all mammalian cells, and its ability to counter both the rhesus and human versions of this host factor is a key component of RhCMV's ability to cross species barriers. Here, we examine the molecular mechanisms that allow this RhCMV antagonist to function against a human restriction factor.

Mining the Potential of Label-Free Biosensors for In Vitro Antipsychotic Drug Screening.

The pharmaceutical industry is facing enormous challenges due to high drug attribution rates. For the past decades, novel methods have been developed for safety and efficacy testing, as well as for improving early development stages. In vitro screening methods for drug-receptor binding are considered to be good alternatives for decreasing costs in the identification of drug candidates. However, these methods require lengthy and troublesome labeling steps. Biosensors hold great promise due to the fact that label-free detection schemes can be designed in an easy and low-cost manner. In this paper, for the first time in the literature, we aimed to compare the potential of label-free optical and impedimetric electrochemical biosensors for the screening of antipsychotic drugs (APDs) based on their binding properties to dopamine receptors. Particularly, we have chosen a currently-used atypical antipsychotic drug (Buspirone) for investigating its dopamine D3 receptor (D3R) binding properties using an impedimetric biosensor and a nanoplasmonic biosensor. Both biosensors have been specifically functionalized and characterized for achieving a highly-sensitive and reliable analysis of drug-D3R binding. Our biosensor strategies allow for comparing different affinities against the D3R, which facilitates the identification of strong or weak dopamine antagonists via in vitro assays. This work demonstrates the unique potential of label-free biosensors for the implementation of cost-efficient and simpler analytical tools for the screening of antipsychotic drugs.

Split versus full tibialis anterior tendon transfer in treatment of residual dynamic supination in treated idiopathic clubfoot by Ponseti method

Background Dynamic supination is a common sequelae following successful nonoperative treatment of clubfoot with the Ponseti technique. It is resulted from a strong tibialis anterior muscle and weak antagonists, particularly the peroneal and tibialis posterior muscles. Tendon-balancing procedure is the most reasonable solution. Use of tibialis anterior tendon transfer (TATT) in recurrent clubfoot deformities has been described since 1940. Patients and methods Through this study, we compare the results of split versus full TATT in the treatment of residual dynamic supination in treated idiopathic clubfoot by Ponseti method. Patients were divided into two groups. The first group (nine patients with 10 feet) (group I) consists of the patients who were managed with split tendon transfer and the second group (nine patients with 10 feet) (group II) consists of the patients who managed with full tendon transfer. Garceau and Palmer’s clinical criteria and a grading system proposed by Thompson and colleagues were used for evaluation of the results of tendon transfer either split or full. Results A total of 18 children (13 males and five females) were involved in this study. The average of the age of the children in group I was 4.3 years and in group II was 4 years at the time of surgery. According to Garceau and Palmer’s clinical criteria, in group I, the preoperative ratings of 10 feet were as follows: four feet were good and six feet were fair, with scores of 3 points and 2 points, respectively. The postoperative ratings were five feet were excellent and five feet were good, with scores of 4 points and 3 points, respectively, with a statistically significant improvement (P 0.05). According to the grading system proposed by Thompson and colleagues for restoration of muscle balance, in group I, eight feet achieved good results and two feet achieved fair results, whereas in group II, seven feet achieved good result and three feet achieved fair results. In comparing the results of both groups, we found there was no statistically significant relation (P>0.05). Conclusion TATT is an excellent method of correcting residual dynamic clubfoot deformity and there is no significant difference in the results by either full transfer or split transfer, and the surgeon’s preference plays a major role in selection of the procedure.

Unique Effects of Clozapine: A Pharmacological Perspective.

Schizophrenia is a heterogenous and severe neuropsychiatric disorder that affects nearly 1% of the population worldwide. Antipsychotic drugs are the mainstay of treatment, but not all patients with schizophrenia respond to treatment with these agents. Clozapine, the first atypical antipsychotic, is a highly effective medication for patients with schizophrenia who do not respond to other antipsychotics. Although clozapine tends not to produce extrapyramidal symptoms, other side effects of the drug (e.g., agranulocytosis, myocarditis, seizures) limit its widespread use. This chapter reviews clozapine's unique clinical effects and unusual pharmacological profile. In addition to its effects in treatment-resistant schizophrenia, clozapine has been shown to decrease suicidality, which occurs at an increased rate in patients with schizophrenia. Still preliminary, but consistent data, also suggest that clozapine limits substance use in these patients, an important effect since substance use disorders are common in patients with schizophrenia and are associated with a poor outcome, including an increased risk for suicide and poor response to treatment. We have suggested, from animal studies, that clozapine's apparent ability to limit substance use may occur through its actions as a weak dopamine D2 receptor antagonist, a potent norepinephrine α-2 receptor antagonist and a norepinephrine reuptake inhibitor. Using animal models, we have built combinations of agents toward creation of safer clozapine-like drugs to reduce substance use in these patients. Future research into the mechanisms of action of clozapine toward the development of safe clozapine-like agents is of great public health importance.

Neuropharmacological classification of antidepressant agents based on their mechanisms of action

The currently available clinical antidepressants can be classified into 13 different classes based on their mechanisms of action. These basic pharmacological concepts thoroughly elucidate and unravel the therapeutic actions and side effects of the wide range of antidepressants currently available. The two classical mechanisms are exhibited by tricyclic antidepressants (TCAs) and by monoamine oxidase inhibitors (MAOIs). Regarding the 11 relatively nonclassical antidepressants, the most widely prescribed agents are the selective serotonin reuptake inhibitors (SSRIs). The mechanisms of action for the other classes of antidepressants that exhibit additional actions on serotonergic neurotransmission are dual serotonin-norepinephrine reuptake inhibition (SNRI), serotonin receptors antagonism with serotonin reuptake inhibition (SARI), serotonin 5-HT1Aautoreceptor partial agonism with serotonin reuptake inhibition (SPARI), serotonin-norepinephrine reuptake inhibition and serotonin receptors antagonism antidepressant with potent antipsychotic D2 receptor blockade/antagonism (SNRISA with potent antipsychotic D2 receptor blockade/antagonism), norepinephrine reuptake inhibition with serotonin receptors antagonism (NRISA), noradrenergic α2-receptor antagonism with specific serotonergic receptors-2 and-3 antagonism (NASSA), and atypical antipsychotics that exhibit weak D2receptor antagonism with potently strong 5-HT2Areceptor blockade. Furthermore, the two classes that exhibit selective norepinephrine reuptake inhibition (NRI) and dual norepinephrine-dopamine reuptake inhibition (NDRI) define separate novel classes of antidepressants that have a direct action on the noradrenergic neurotransmission system but have no direct action on the serotonergic neurotransmission system, while the last remaining one class of N-methyl-D-aspartate-glutamatergic ionoceptor antagonist/inverse agonist/partial agonist also represents a separate novel class of antidepressants with a direct action on the excitatory glutamatergic neurotransmission system but no direct action on the serotonergic, noradrenergic, or dopaminergic neurotransmission systems. Lastly, this review remarkably advocates for the incorporation of the atypical antipsychotics and NMDA-glutamatergic ionoceptor antagonist/inverse agonist/partial agonist as new member classes of the antidepressant agents because of their clinically significant roles in the management of depression disorders.

Inhibition coefficient and molecular diversity of multi stress tolerant Trichoderma as potential biocontrol agent against Sclerotium rolfsii Sacc.

Trichoderma is one of the most exploited biocontrol agent for the management of plant diseases. Twenty strains of Trichoderma (six of T. harzianum, four of T. viride, three of T. virens, three of T. koningii, each one of T. hamatum, T. reesei, T. parceramosum and Trichoderma spp.) subjected to in vitro antagonism up to 12days after inoculation against Sclerotium rolfsii Sacc. causing stem rot in groundnut. A new concept was developed to determine inhibition coefficient representing pathogen biology and biocontrol related biophysical variables. Results explained differential inhibition coefficient of test pathogen by Trichoderma antagonists. The inhibition coefficient of test pathogen was examined highest (91.13%) by T. virens NBAII Tvs12 followed by T. virens MTCC 794 (89.33%) and T. koningii MTCC 796 (62.39%). Microscopic study confirmed biocontrol mechanism as mycoparasitism for Tvs12 and antibiosis for T. koningii MTCC 796. The sclerotial biogenesis of test pathogen was elevated during weak antagonism and diminished in interactions with strong antagonists. The inhibition coefficient of S. rolfsii was significantly negatively correlated with sclerotia formation and lipid peroxidation during the antagonism. Trichoderma strains were screened for fungicides (carbendazim and tebuconazole, thiram and mancozeb) and abiotic stress (drought and salt) tolerance. Results indicated that T. koningii MTCC 796 efficiently grew better than the other strains with maximum radial growth under adverse conditions. The genetic variability among the Trichoderma was determined using 34 gene specific markers which amplified 146 alleles. The SSR similarities explained substantial diversity (15 to 87%) across Trichoderma strains and pathogen S. rolfsii. Principal coordinates analysis (PCA) were comparable to the cluster analysis and first three most informative PC components explained 64.45% of the total variation. In PCA, potent antagonists appear to be distinct from other strains. Five SSR markers T1F/T1R(311), TvCTT56f/TvCTT56r(387), TvGAT18f/TvGAT18r(364), TvCA39f/TvCA39r(196) and TvAG29f/TvAG29r(418) found to be unique to distinguish best antagonist strain Tvs12. However, MTCC 796 was examined most stress tolerant strain with better inhibition coefficient which might be useful to control the disease under adverse conditions or as a part of integrated pest management.

Incorporation of dihydroartemisinin into memantine through a propriate spacer to make hybrid with enhanced effects to protect PC12 cells from corticosterone-caused impairments

Ten memantine(Mema)-dihydroartemisinin(DHA) ligands were designed and synthesized. Three types of isomers including α, β, and a defined γ isomer were found in each intermediates(1a—1e). Type γ isomer was firstly reported here and confirmed as a less stable eclipsed conformation. The bonding of Mema with DHA through different carbon chains generally makes the new entities more cytotoxic than either Mema or artemisinin(Arte). The β Mema/DHA ligands are a little bit more cytotoxic than α ligands. By applying corticosterone(Cort)-impaired PC12 cells models, it was found that Mema and those ligands with more than 3 carbon chains showed weak or no neuro-protective activities against the insults. However, two ligands, 2a(β) and 2b(β) showed better effects than either Arte or their combination(Mema/Arte in 1:1 molar ratio) at a dose of 5 µmol/L. Furthermore, ligands 2a(β), 2b(β) and 2c(β) were confirmed as mild N-methyl-D-aspartate(NMDA) antagonists, and their corresponding α isomers are weak NMDA antagonists. All the data indicate that the bonding of Mema/DHA in compacted β conformation mode results in enhanced effects against Cort-induced insults in PC12 cells and might reverse memantine as an anti-depression NMDA antagonist.

Structural insight into allosteric modulation of protease-activated receptor 2.

Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation. PARs have been the subject of major pharmaceutical research efforts but the discovery of small-molecule antagonists that effectively bind them has proved challenging. The only marketed drug targeting a PAR is vorapaxar, a selective antagonist of PAR1 used to prevent thrombosis. The structure of PAR1 in complex with vorapaxar has been reported previously. Despite sequence homology across the PAR isoforms, discovery of PAR2 antagonists has been less successful, although GB88 has been described as a weak antagonist. Here we report crystal structures of PAR2 in complex with two distinct antagonists and a blocking antibody. The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. Functional and binding studies reveal that AZ8838 exhibits slow binding kinetics, which is an attractive feature for a PAR2 antagonist competing against a tethered ligand. Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. We also show that a blocking antibody antigen-binding fragment binds to the extracellular surface of PAR2, preventing access of the tethered ligand to the peptide-binding site. These structures provide a basis for the development of selective PAR2 antagonists for a range of therapeutic uses.

Neurochemical arguments for the use of dopamine D4 receptor stimulation to improve cognitive impairment associated with schizophrenia

BackgroundDopamine (DA) D4 receptors have been implicated in schizophrenia and the ability of some atypical antipsychotic drugs (APDs) to improve the cognitive impairment associated with schizophrenia (CIAS). Systemic administration of a D4 agonist, PD168077, at a sub-effective dose, together with a sub-effective dose of lurasidone, an atypical APD which is a weak D4 receptor antagonist, reversed the deficit in novel object recognition (NOR) in rats treated subchronically with phencyclidine (PCP), a rodent model of CIAS. Atypical APDs potentially stimulate D4Rs via their ability to enhance DA release in key brain areas related to cognition. However, some atypical APDs are relatively potent D4 antagonists at clinical dosages, including clozapine, and risperidone. The D4 antagonist, L745870, blocked the ability of clozapine, but not lurasidone, to reverse the NOR deficit in rats. MethodsThe purpose of this study was to determine the effects of a selective D4 agonist and antagonist, alone, and as pretreatment with lurasidone, on neurotransmitter efflux in mouse medial prefrontal cortex (mPFC) and dorsal striatum (dSTR), using in vivo microdialysis. Results and discussionPD168077 alone, and in combination with sub-effective dose lurasidone, increased DA and acetylcholine (ACh) efflux in mPFC, but only DA efflux in dSTR. L745870 had no effect on neurotransmitter efflux on its own or on the ability of lurasidone to increase cortical or striatal neurotransmitter efflux. These results indicate D4 receptor agonism alone is sufficient to increase cortical DA and ACh efflux without interfering with the effects of lurasidone and possibly other atypical APDs on extracellular cortical DA and ACh levels. A D4 agonist may be useful for treating CIAS, especially as augmentation of those atypical APDs which are not potent D4 antagonists.

N6-Substituted 5'-N-Methylcarbamoyl-4'-selenoadenosines as Potent and Selective A3 Adenosine Receptor Agonists with Unusual Sugar Puckering and Nucleobase Orientation.

Potent and selective A3 adenosine receptor (AR) agonists were identified by the replacement of 4'-oxo- or 4'-thionucleosides with bioisosteric selenium. Unlike previous agonists, 4'-seleno analogues preferred a glycosidic syn conformation and South sugar puckering, as shown in the X-ray crystal structure of 5'-N-methylcarbamoyl derivative 3p. Among the compounds tested, N6-3-iodobenzyl analogue 3d was found to be the most potent A3AR full agonist (Ki = 0.57 nM), which was ≥800- and 1900-fold selective for A1AR and A2AAR, respectively. In the N6-cycloalkyl series, 2-Cl analogues generally exhibited better hA3AR affinity than 2-H analogues, whereas 2-H > 2-Cl in the N6-3-halobenzyl series. N7 isomers 3t and 3u were much weaker in binding than corresponding N9 isomers, but compound 3t lacked A3AR activation, appearing to be a weak antagonist. 2-Cl-N6-3-iodobenzyl analogue 3p inhibited chemoattractant-induced migration of microglia/monocytes without inducing cell death at ≤50 μM. This suggests the potential for the development of 4'-selenonucleoside A3AR agonists as novel antistroke agents.

The scaffold protein RACK1 is a target of endocrine disrupting chemicals (EDCs) with important implication in immunity

We recently demonstrated the existence of a complex hormonal balance between steroid hormones in the control of RACK1 (Receptor for Activated C Kinase 1) expression and immune activation, suggesting that this scaffold protein may also be targeted by endocrine disrupting chemicals (EDCs). As a proof of concept, we investigated the effect of the doping agent nandrolone, an androgen receptor (AR) agonist, and of p,p′DDT (dichlorodiphenyltrichloroethane) and its main metabolite p,p′DDE (dichlorodiphenyldichloroethylene), a weak and strong AR antagonist, respectively, on RACK1 expression and innate immune response. In analogy to endogenous androgens, nandrolone induced a dose-related increase in RACK1 transcriptional activity and protein expression, resulting in increased LPS-induced IL-8 and TNF-α production and proliferation in THP-1 cells. Conversely, p,p′DDT and p,p′DDE significantly decrease RACK1 expression, LPS-induced cytokine production and CD86 expression; with p,p′DDE exerting a stronger repressor effect than p,p′DDT, consistent with its stronger AR antagonistic effect. These results indicate that RACK1 could be a relevant target of EDCs, responding in opposite ways to agonist or antagonist of AR, representing a bridge between the endocrine system and the innate immune system.

Substituted 2-Aminopyrimidines Selective for α7-Nicotinic Acetylcholine Receptor Activation and Association with Acetylcholine Binding Proteins.

Through studies with ligand binding to the acetylcholine binding protein (AChBP), we previously identified a series of 4,6-substituted 2-aminopyrimidines that associate with this soluble surrogate of the nicotinic acetylcholine receptor (nAChR) in a cooperative fashion, not seen for classical nicotinic agonists and antagonists. To examine receptor interactions of this structural family on ligand-gated ion channels, we employed HEK cells transfected with cDNAs encoding three requisite receptor subtypes: α7-nAChR, α4β2-nAChR, and a serotonin receptor (5-HT3AR), along with a fluorescent reporter. Initial screening of a series of over 50 newly characterized 2-aminopyrimidines with affinity for AChBP showed only two to be agonists on the α7-nAChR below 10 μM concentration. Their unique structural features were incorporated into design of a second subset of 2-aminopyrimidines yielding several congeners that elicited α7 activation with EC50 values of 70 nM and Kd values for AChBP in a similar range. Several compounds within this series exhibit specificity for the α7-nAChR, showing no activation or antagonism of α4β2-nAChR or 5-HT3AR at concentrations up to 10 μM, while others were weaker antagonists (or partial agonists) on these receptors. Analysis following cocrystallization of four ligand complexes with AChBP show binding at the subunit interface, but with an orientation or binding pose that differs from classical nicotinic agonists and antagonists and from the previously analyzed set of 2-aminopyrimidines that displayed distinct cooperative interactions with AChBP. Orientations of aromatic side chains of these complexes are distinctive, suggesting new modes of binding at the agonist-antagonist site and perhaps an allosteric action for heteromeric nAChRs.

Highly Potent Non-Carboxylic Acid Autotaxin Inhibitors Reduce Melanoma Metastasis and Chemotherapeutic Resistance of Breast Cancer Stem Cells.

Autotaxin (ATX, aka. ENPP2) is the main source of the lipid mediator lysophosphatidic acid (LPA) in biological fluids. This study reports on inhibitors of ATX derived by lead optimization of the benzene-sulfonamide in silico hit compound 3. The new analogues provide a comprehensive structure-activity relationship of the benzene-sulfonamide scaffold that yielded a series of highly potent ATX inhibitors. The three most potent analogues (3a, IC50 ∼ 32 nM; 3b, IC50 ∼ 9 nM; and 14, IC50 ∼ 35 nM) inhibit ATX-dependent invasion of A2058 human melanoma cells in vitro. Two of the most potent compounds, 3b and 3f (IC50 ∼ 84 nM), lack inhibitory action on ENPP6 and ENPP7 but possess weak antagonist action specific to the LPA1 G protein-coupled receptor. In particular, compound 3b potently reduced in vitro chemotherapeutic resistance of 4T1 breast cancer stem-like cells to paclitaxel and significantly reduced B16 melanoma metastasis in vivo.

Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review

BackgroundSchizophrenia is a highly heterogeneous disorder, and around a third of patients are treatment-resistant. The only evidence-based treatment for these patients is clozapine, an atypical antipsychotic with relatively weak dopamine antagonism. It is plausible that varying degrees of response to antipsychotics reflect categorically distinct illness subtypes, which would have significant implications for research and clinical practice. If these subtypes could be distinguished at illness onset, this could represent a first step towards personalised medicine in psychiatry. This systematic review investigates whether current evidence supports conceptualising treatment-resistant and treatment-responsive schizophrenoa as categorically distinct subtypes.MethodA systematic literature search was conducted, using PubMed, EMBASE, PsycInfo, CINAHL and OpenGrey databases, to identify all studies which compared treatment-resistant schizophrenia (defined as either a lack of response to two antipsychotic trials or clozapine prescription) to treatment-responsive schizophrenia (defined as known response to non-clozapine antipsychotics).ResultsNineteen studies of moderate quality met inclusion criteria. The most robust findings indicate that treatment-resistant patients show glutamatergic abnormalities, a lack of dopaminergic abnormalities, and significant decreases in grey matter compared to treatment-responsive patients. Treatment-resistant patients were also reported to have higher familial loading; however, no individual gene-association study reported their findings surviving correction for multiple comparisons.ConclusionsTentative evidence supports conceptualising treatment-resistant schizophrenia as a categorically different illness subtype to treatment-responsive schizophrenia. However, research is limited and confirmation will require replication and rigorously controlled studies with large sample sizes and prospective study designs.