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Previous research has shown that resveratrol can increase cerebral blood flow (CBF) in the absence of improved cognitive performance in healthy, young human subjects during the performance of cognitively demanding tasks. This lack of cognitive effects may be due to low bioavailability and, in turn, reduced bioefficacy of resveratrol in vivo. Piperine can alter polyphenol pharmacokinetics, but previous studies have not investigated whether this affects the efficacy of the target compound. Therefore, the objective of the present study was to ascertain whether co-supplementation of piperine with resveratrol affects the bioavailability and efficacy of resveratrol with regard to cognition and CBF. The present study utilised a randomised, double-blind, placebo-controlled, within-subjects design, where twenty-three adults were given placebo, trans-resveratrol (250 mg) and trans-resveratrol with 20 mg piperine on separate days at least a week apart. After a 40 min rest/absorption period, the participants performed a selection of cognitive tasks and CBF was assessed throughout the period, in the frontal cortex, using near-IR spectroscopy. The presence of resveratrol and its conjugates in the plasma was confirmed by liquid chromatography–MS analysis carried out following the administration of the same doses in a separate cohort (n 6). The results indicated that when co-supplemented, piperine and resveratrol significantly augmented CBF during task performance in comparison with placebo and resveratrol alone. Cognitive function, mood and blood pressure were not affected. The plasma concentrations of resveratrol and its metabolites were not significantly different between the treatments, which indicates that co-supplementation of piperine with resveratrol enhances the bioefficacy of resveratrol with regard to CBF effects, but not cognitive performance, and does this without altering bioavailability.

Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-α pathways, respectively. Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2 could ameliorate obesity-related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds, AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 in vitro . AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-α pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes. An orally active small molecule, AdipRon, that binds to and activates both adiponectin receptors (AdipoR1 and AdipoR2) is identified; it ameliorates diabetes in mice on a high-fat diet and in genetically obese db / db mice, and if this can be extrapolated to humans, orally active agonists such as AdipoRon are a promising new approach to treat obesity-related diseases such as type 2 diabetes. AdipRon, a small molecule with antidiabetic activity Adiponectin is a fat-derived hormone that seems to have a crucial role in the protection from insulin resistance/diabetes and atherosclerosis. This study identifies an orally active compound, obtained by screening small molecules in the chemical library at the University of Tokyo's Open Innovation Center for Drug Discovery, that binds to and activates the AdipoR1 and AdipoR2 receptors that mediate adiponectin's antidiabetic action. Named AdipRon, the compound ameliorates insulin resistance and glucose intolerance in mice on a high-fat diet and in genetically obese mice. AdipoRon also extends the shortened lifespan of db / db mice on a high-fat diet. If this work can be extrapolated to humans, orally active agonists such as AdipoRon could offer a promising new approach to treat obesity-related diseases such as type 2 diabetes.

Rationale JNJ-37822681 is a highly selective, fast dissociating dopamine D 2 -receptor antagonist being developed for the treatment of schizophrenia. A single dose [ 11 C]raclopride positron emission tomography (PET) imaging study had yielded an estimated clinical dose range. Receptor occupancy at steady state was explored to test the validity of the single-dose estimates during chronic treatment. Objectives The aims of this study are to characterize single and multiple dose pharmacokinetics and obtain striatal D 2 -receptor occupancies to predict doses for efficacy studies and assess the safety and tolerability of JNJ-37822681. Methods An open-label single- and multiple-dose study with 10 mg JNJ-37822681 (twice daily for 13 doses) was performed in 12 healthy men. Twenty [ 11 C]raclopride PET scans (up to 60 h after the last dose) from 11 subjects were used to estimate D 2 -receptor occupancy. A direct effect O max model was applied to explore the relationship between JNJ-37822681 plasma concentration and striatal D 2 -receptor occupancy. Results Steady state was reached after 4–5 days of twice daily dosing. JNJ-37822681 plasma concentrations of 3.17 to 63.0 ng/mL resulted in D 2 occupancies of 0 % to 62 %. The concentration leading to 50 % occupancy was 18.5 ng/mL (coefficient of variation 3.9 %) after single dose and 26.0 ng/mL (8.2 %) at steady state. JNJ-37822681 was well tolerated. Conclusions Receptor occupancy after single dose and at steady state differed for JNJ-37822681 and the robustness of the estimates at steady state will be tested in phase 2 studies. Dose predictions indicated that 10, 20, and 30 mg JNJ-37822681 twice daily could be suitable for these studies.

The human σ 1 receptor is an enigmatic endoplasmic-reticulum-resident transmembrane protein implicated in a variety of disorders including depression, drug addiction, and neuropathic pain 1 . Recently, an additional connection to amyotrophic lateral sclerosis has emerged from studies of human genetics and mouse models 2 . Unlike many transmembrane receptors that belong to large, extensively studied families such as G-protein-coupled receptors or ligand-gated ion channels, the σ 1 receptor is an evolutionary isolate with no discernible similarity to any other human protein. Despite its increasingly clear importance in human physiology and disease, the molecular architecture of the σ 1 receptor and its regulation by drug-like compounds remain poorly defined. Here we report crystal structures of the human σ 1 receptor in complex with two chemically divergent ligands, PD144418 and 4-IBP. The structures reveal a trimeric architecture with a single transmembrane domain in each protomer. The carboxy-terminal domain of the receptor shows an extensive flat, hydrophobic membrane-proximal surface, suggesting an intimate association with the cytosolic surface of the endoplasmic reticulum membrane in cells. This domain includes a cupin-like β-barrel with the ligand-binding site buried at its centre. This large, hydrophobic ligand-binding cavity shows remarkable plasticity in ligand recognition, binding the two ligands in similar positions despite dissimilar chemical structures. Taken together, these results reveal the overall architecture, oligomerization state, and molecular basis for ligand recognition by this important but poorly understood protein. The X-ray crystal structures of the human σ1 receptor bound to two different ligands are reported, revealing the overall architecture, oligomerization state, and molecular basis for ligand recognition by this protein. Structure of human σ1 receptor The human σ1 receptor is a transmembrane protein of the endoplasmic reticulum that is implicated in depression, drug addiction and neurodegenerative disorders including amyotrophic lateral sclerosis. In this manuscript, the authors report X-ray crystal structures of the human σ1 receptor in the presence of two different ligands. The structure of the protein is trimeric, with a single transmembrane domain in each protomer. Despite having dissimilar chemical structures, both ligands bind to the same site, a large, hydrophobic cavity. Taken together, these results reveal the overall architecture, oligomerization state, and molecular basis for ligand recognition by this important, but poorly understood, protein.

The crystal structure of the human nociceptin/orphanin FQ peptide receptor in complex with the peptide mimetic antagonist compound-24 is determined, with potential importance for the development of new therapeutic agents. Where opiates hit home Four papers in this issue of Nature present the long-awaited high-resolution crystal structures of the four known opioid receptors in ligand-bound conformations. These G-protein-coupled receptors are the targets of a broad range of drugs, including painkillers, antidepressants, anti-anxiety agents and anti-addiction medications. Brian Kobilka’s group reports the crystal structure of the µ-opioid receptor bound to a morphinan antagonist and the δ-opioid receptor bound to naltrindole. Raymond Stevens’ group reports on the κ-opioid receptor bound to the selective antagonist JDTic, and the nociceptin/orphanin FQ receptor bound to a peptide mimetic. In an associated News and Views, Marta Filizola and Lakshmi Devi discuss the implications of these landmark papers for research on the mechanisms underlying receptor function and drug development. Members of the opioid receptor family of G-protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system, where they have key roles in nociception and analgesia. Unlike the ‘classical’ opioid receptors, δ, κ and μ (δ-OR, κ-OR and μ-OR), which were delineated by pharmacological criteria in the 1970s and 1980s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, also known as ORL-1) was discovered relatively recently by molecular cloning and characterization of an orphan GPCR 1 . Although it shares high sequence similarity with classical opioid GPCR subtypes (∼60%), NOP has a markedly distinct pharmacology, featuring activation by the endogenous peptide N/OFQ, and unique selectivity for exogenous ligands 2 , 3 . Here we report the crystal structure of human NOP, solved in complex with the peptide mimetic antagonist compound-24 (C-24) (ref. 4 ), revealing atomic details of ligand–receptor recognition and selectivity. Compound-24 mimics the first four amino-terminal residues of the NOP-selective peptide antagonist UFP-101, a close derivative of N/OFQ, and provides important clues to the binding of these peptides. The X-ray structure also shows substantial conformational differences in the pocket regions between NOP and the classical opioid receptors κ (ref. 5 ) and μ (ref. 6 ), and these are probably due to a small number of residues that vary between these receptors. The NOP–compound-24 structure explains the divergent selectivity profile of NOP and provides a new structural template for the design of NOP ligands.

Phosphorylation of G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) desensitizes G-protein signalling and promotes arrestin signalling, which is also modulated by biased ligands 1 – 6 . The molecular assembly of GRKs on GPCRs and the basis of GRK-mediated biased signalling remain largely unknown owing to the weak GPCR–GRK interactions. Here we report the complex structure of neurotensin receptor 1 (NTSR1) bound to GRK2, Gα q and the arrestin-biased ligand SBI-553 7 . The density map reveals the arrangement of the intact GRK2 with the receptor, with the N-terminal helix of GRK2 docking into the open cytoplasmic pocket formed by the outward movement of the receptor transmembrane helix 6, analogous to the binding of the G protein to the receptor. SBI-553 binds at the interface between GRK2 and NTSR1 to enhance GRK2 binding. The binding mode of SBI-553 is compatible with arrestin binding but clashes with the binding of Gα q protein, thus providing a mechanism for its arrestin-biased signalling capability. In sum, our structure provides a rational model for understanding the details of GPCR–GRK interactions and GRK2-mediated biased signalling. Structural studies on the complex containing G-protein-coupled receptor kinase 2 (GRK2), neurotensin receptor 1 (NTSR1), Gα q and the arrestin-biased ligand SBI-553 provide insights into these interactions and a foundation for the design of arrestin-biased ligands for G-protein-coupled receptors.

Activating mutations in PTPN11 , encoding the cytosolic protein tyrosine phosphatase SHP2, result in developmental disorders and act as oncogenic drivers in patients with hematologic cancers. The allosteric inhibitor SHP099 stabilizes the wild-type SHP2 enzyme in an autoinhibited conformation that is itself destabilized by oncogenic mutations. Here, we report the impact of the highly activated and most frequently observed mutation, E76K, on the structure of SHP2, and investigate the effect of E76K and other oncogenic mutations on allosteric inhibition by SHP099. SHP2 E76K adopts an open conformation but can be restored to the closed, autoinhibited conformation, near-identical to the unoccupied wild-type enzyme, when complexed with SHP099. SHP099 inhibitory activity against oncogenic SHP2 variants in vitro and in cells scales inversely with the activating strength of the mutation, indicating that either oncoselective or vastly more potent inhibitors will be necessary to suppress oncogenic signaling by the most strongly activating SHP2 mutations in cancer. Activating mutations of the non-receptor protein tyrosine phosphatase SHP2 can cause cancer. Here the authors present the crystal structure of SHP2 E76K , the most frequent cancer-associated SHP2 mutation, which adopts an open-state structure and show that the allosteric inhibitor SHP099 can revert SHP2 E76K to its closed, autoinhibited conformation.

Black pepper (Piper nigrum L.) has been employed in medicine (epilepsy, headaches, and diabetes), where its effects are mainly attributed to a nitrogen alkaloid called piperidine (1-(1-[1,3-benzodioxol-5-yl]-1-oxo-2,4 pentenyl) piperidine). Piperine co-administered with vitamins and minerals has improved its absorption. Therefore, this study aimed to describe the impact of the joint administration of iron (Fe) plus black pepper in physically active healthy individuals. Fe is a micronutrient that aids athletic performance by influencing the physiological functions involved in endurance sports by improving the transport, storage, and utilization of oxygen. Consequently, athletes have risk factors for Fe depletion, Fe deficiency, and eventually, anemia, mainly from mechanical hemolysis, gastrointestinal disturbances, and loss of Fe through excessive sweating. Declines in Fe stores have been reported to negatively alter physical capacities such as aerobic capacity, strength, and skeletal muscle recovery in elite athletes. Thus, there is a need to maintain Fe storage, even if Fe intake meets the recommended daily allowance (RDA), and Fe supplementation may be justified in physically active individuals, in states of Fe deficiency, with or without anemia. Females, in particular, should monitor their Fe hematological profile. The recommended oral Fe supplements are ferrous or ferric salts, sulfate, fumarate, and gluconate. These preparations constitute the first line of treatment; however, the high doses administered have gastrointestinal side effects that reduce tolerance and adherence to treatment. Thus, a strategy to counteract these adverse effects is to improve the bioavailability of Fe. Therefore, piperine may benefit the absorption of Fe through its bioavailability enhancement properties. Three research studies of Fe associated with black pepper have reported improvements in parameters related to the metabolism of Fe, without adverse effects. Although more research is needed, this could represent an advance in oral Fe supplementation for physically active individuals.

Targeting NMDA receptors Ifenprodil, a phenylethanolamine first developed as an adrenergic antagonist and now widely used as an antihypertensive, also has a neuroprotective effect through receptors. A study of this interaction shows that the NMDA receptor subunits GluN1 and GluN2B form heterodimers that bind ifenprodil at the GluN1/GluN2B interface. Conformational mobility in the GluN2B amino-terminal domain is essential for ifenprodil-mediated inhibition of the NMDA receptors. These findings may be relevant to the design of therapeutics to target specific NMDA receptor subtypes for use in neurological disorders. Since it was discovered that the anti-hypertensive agent ifenprodil has neuroprotective activity through its effects on NMDA ( N -methyl-D-aspartate) receptors 1 , a determined effort has been made to understand the mechanism of action and to develop improved therapeutic compounds on the basis of this knowledge 2 , 3 , 4 . Neurotransmission mediated by NMDA receptors is essential for basic brain development and function 5 . These receptors form heteromeric ion channels and become activated after concurrent binding of glycine and glutamate to the GluN1 and GluN2 subunits, respectively. A functional hallmark of NMDA receptors is that their ion-channel activity is allosterically regulated by binding of small compounds to the amino-terminal domain (ATD) in a subtype-specific manner. Ifenprodil and related phenylethanolamine compounds, which specifically inhibit GluN1 and GluN2B NMDA receptors 6 , 7 , have been intensely studied for their potential use in the treatment of various neurological disorders and diseases, including depression, Alzheimer’s disease and Parkinson’s disease 2 , 4 . Despite considerable enthusiasm, mechanisms underlying the recognition of phenylethanolamines and ATD-mediated allosteric inhibition remain limited owing to a lack of structural information. Here we report that the GluN1 and GluN2B ATDs form a heterodimer and that phenylethanolamine binds at the interface between GluN1 and GluN2B, rather than within the GluN2B cleft. The crystal structure of the heterodimer formed between the GluN1b ATD from Xenopus laevis and the GluN2B ATD from Rattus norvegicus shows a highly distinct pattern of subunit arrangement that is different from the arrangements observed in homodimeric non-NMDA receptors and reveals the molecular determinants for phenylethanolamine binding. Restriction of domain movement in the bi-lobed structure of the GluN2B ATD, by engineering of an inter-subunit disulphide bond, markedly decreases sensitivity to ifenprodil, indicating that conformational freedom in the GluN2B ATD is essential for ifenprodil-mediated allosteric inhibition of NMDA receptors. These findings pave the way for improving the design of subtype-specific compounds with therapeutic value for neurological disorders and diseases.

Protein tyrosine phosphatase SHP2 functions as a key regulator of cell cycle control, and activating mutations cause several cancers. Here, we dissect the energy landscape of wild-type SHP2 and the oncogenic mutation E76K. NMR spectroscopy and X-ray crystallography reveal that wild-type SHP2 exchanges between closed, inactive and open, active conformations. E76K mutation shifts this equilibrium toward the open state. The previously unknown open conformation is characterized, including the active-site WPD loop in the inward and outward conformations. Binding of the allosteric inhibitor SHP099 to E76K mutant, despite much weaker, results in an identical structure as the wild-type complex. A conformational selection to the closed state reduces drug affinity which, combined with E76K’s much higher activity, demands significantly greater SHP099 concentrations to restore wild-type  activity levels. The differences in structural ensembles and drug-binding kinetics of cancer-associated SHP2 forms may stimulate innovative ideas for developing more potent inhibitors for activated SHP2 mutants. The protein tyrosine phosphatase SHP2 is a key regulator of cell cycle control. Here the authors combine NMR measurements and X-ray crystallography and show that wild-type SHP2 dynamically exchanges between a closed inactive conformation and an open activated form and that the oncogenic E76K mutation shifts the equilibrium to the open state, which is reversed by binding of the allosteric inhibitor SHP099.