From α4β2 Nicotinic Ligands to the Discovery of σ1 Receptor Ligands: Pharmacophore Analysis and Rational Design.
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ABSTRACT:
SUBMITTER: Yu LF
PROVIDER: S-EPMC3638970 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The neuronal nicotinic acetylcholine receptors (nAChRs) belong to the ligand-gated ion channel (GLIC) group, presenting a crucial role in several biological processes and neuronal disorders. The α4β2 and α7 nAChRs are the most abundant in the central nervous system (CNS), being involved in challenging diseases such as epilepsy, Alzheimer's disease, schizophrenia, and anxiety disorder, as well as alcohol and nicotine dependencies. In addition, in silico-based strategies may contribute to revealing new insights into drug design and virtual screening to find new drug candidates to treat CNS disorders. In this context, the pharmacophore maps were constructed and validated for the orthosteric sites of α4β2 and α7 nAChRs, through a docking-based Comparative Intermolecular Contacts Analysis (dbCICA). In this sense, bioactive ligands were retrieved from the literature for each receptor. A molecular docking protocol was developed for all ligands in both receptors by using GOLD software, considering GoldScore, ChemScore, ASP, and ChemPLP scoring functions. Output GOLD results were post-processed through dbCICA to identify critical contacts involved in protein-ligand interactions. Moreover, Crossminer software was used to construct a pharmacophoric map based on the most well-behaved ligands and negative contacts from the dbCICA model for each receptor. Both pharmacophore maps were validated by using a ROC curve. The results revealed important features for the ligands, such as the presence of hydrophobic regions, a planar ring, and hydrogen bond donor and acceptor atoms for α4β2. Parallelly, a non-planar ring region was identified for α7. These results can enable fragment-based drug design (FBDD) strategies, such as fragment growing, linking, and merging, allowing an increase in the activity of known fragments. Thus, our results can contribute to a further understanding of structural subunits presenting the potential for key ligand-receptor interactions, favoring the search in molecular databases and the design of novel ligands.
| S-EPMC9735964 | biostudies-literature
Project description:Nicotinic acetylcholine receptors are ligand-gated ion channels that mediate fast chemical neurotransmission at the neuromuscular junction and have diverse signalling roles in the central nervous system. The nicotinic receptor has been a model system for cell-surface receptors, and specifically for ligand-gated ion channels, for well over a century. In addition to the receptors' prominent roles in the development of the fields of pharmacology and neurobiology, nicotinic receptors are important therapeutic targets for neuromuscular disease, addiction, epilepsy and for neuromuscular blocking agents used during surgery. The overall architecture of the receptor was described in landmark studies of the nicotinic receptor isolated from the electric organ of Torpedo marmorata. Structures of a soluble ligand-binding domain have provided atomic-scale insights into receptor-ligand interactions, while high-resolution structures of other members of the pentameric receptor superfamily provide touchstones for an emerging allosteric gating mechanism. All available high-resolution structures are of homopentameric receptors. However, the vast majority of pentameric receptors (called Cys-loop receptors in eukaryotes) present physiologically are heteromeric. Here we present the X-ray crystallographic structure of the human α4β2 nicotinic receptor, the most abundant nicotinic subtype in the brain. This structure provides insights into the architectural principles governing ligand recognition, heteromer assembly, ion permeation and desensitization in this prototypical receptor class.
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Project description:Despite their controversial physiology, sigma-1 (σ1) receptors are intriguing targets for the development of therapeutic agents for central nervous system diseases. With the aim of providing versatile pharmacological tools to study σ1 receptors, we developed three σ1 fluorescent tracers by functionalizing three well characterized σ1 ligands with a fluorescent tag. A good compromise between σ1 binding affinity and fluorescent properties was reached, and the σ1 specific targeting of the novel tracers was demonstrated by confocal microscopy and flow cytometry. These novel ligands were also successfully used in competition binding studies by flow cytometry, showing their utility in nonradioactive binding assays as an alternative strategy to the more classical radioligand binding assays. To the best of our knowledge these are the first σ1 fluorescent ligands to be developed and successfully employed in living cells, representing promising tools to strengthen σ1 receptors related studies.
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Project description:Interest in nicotinic acetylcholine receptor (nAChR) ligands as potential therapeutic agents for cognitive disorders began more than 30 years ago when it was first demonstrated that the tobacco alkaloid nicotine could improve cognitive function in nicotine-deprived smokers as well as nonsmokers. Numerous animal and human studies now indicate that nicotine and a variety of nAChR ligands have the potential to improve multiple domains of cognition including attention, spatial learning, working memory, recognition memory, and executive function. The purpose of this review is to (1) discuss several pharmacologic strategies that have been developed to enhance nAChR activity (eg, agonist, partial agonist, and positive allosteric modulator) and improve cognitive function, (2) provide a brief overview of some of the more common rodent behavioral tasks with established translational validity that have been used to evaluate nAChR ligands for effects on cognitive function, and (3) briefly discuss some of the topics of debate regarding the development of optimal therapeutic strategies using nAChR ligands. Because of their densities in the mammalian brain and the amount of literature available, the review primarily focuses on ligands of the high-affinity ?4?2* nAChR ("*" indicates the possible presence of additional subunits in the complex) and the low-affinity ?7 nAChR. The behavioral task discussion focuses on representative methods that have been designed to model specific domains of cognition that are relevant to human neuropsychiatric disorders and often evaluated in human clinical trials. IMPLICATIONS:The preclinical literature continues to grow in support of the development of nAChR ligands for a variety of illnesses that affect humans. However, to date, no new nAChR ligand has been approved for any condition other than nicotine dependence. As discussed in this review, the studies conducted to date provide the impetus for continuing efforts to develop new nAChR strategies (ie, beyond simple agonist and partial agonist approaches) as well as to refine current behavioral strategies and create new animal models to address translational gaps in the drug discovery process.
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Project description:Desformylflustrabromine (dFBr; 1), perhaps the first selective positive allosteric modulator of α4β2 neuronal nicotinic acetylcholine (nACh) receptors, was deconstructed to determine which structural features contribute to its actions on receptors expressed in Xenopus ooycytes using two-electrode voltage clamp techniques. Although the intact structure of 1 was found to be optimal, several deconstructed analogs retained activity. Neither the 6-bromo substituent nor the entire 2-position chain is required for activity. In particular, reduction of the olefinic side chain of 1, as seen with 6, not only resulted in retention of activity/potency but in enhanced selectivity for α4β2 versus α7 nACh receptors. Pharmacophoric features for the allosteric modulation of α4β2 nACh receptors by 1 were identified.
| S-EPMC3200116 | biostudies-literature
Project description:Fast chemical communication in the nervous system is mediated by neurotransmitter-gated ion channels. The prototypical member of this class of cell surface receptors is the cation-selective nicotinic acetylcholine receptor. As with most ligand-gated ion channels, nicotinic receptors assemble as oligomers of subunits, usually as hetero-oligomers and often with variable stoichiometries 1 . This intrinsic heterogeneity in protein composition provides fine tunability in channel properties, which is essential to brain function, but frustrates structural and biophysical characterization. The α4β2 subtype of the nicotinic acetylcholine receptor is the most abundant isoform in the human brain and is the principal target in nicotine addiction. This pentameric ligand-gated ion channel assembles in two stoichiometries of α- and β-subunits (2α:3β and 3α:2β). Both assemblies are functional and have distinct biophysical properties, and an imbalance in the ratio of assemblies is linked to both nicotine addiction2,3 and congenital epilepsy4,5. Here we leverage cryo-electron microscopy to obtain structures of both receptor assemblies from a single sample. Antibody fragments specific to β2 were used to 'break' symmetry during particle alignment and to obtain high-resolution reconstructions of receptors of both stoichiometries in complex with nicotine. The results reveal principles of subunit assembly and the structural basis of the distinctive biophysical and pharmacological properties of the two different stoichiometries of this receptor.
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Project description:The σ1 receptor (σ1-R) is an enigmatic endoplasmic reticulum resident transmembrane protein implicated in a variety of central nervous system disorders and whose agonists have neuroprotective activity. In spite of σ1-R's physio-pathological and pharmacological importance, two of the most important features required to fully understand σ1-R function, namely the receptor endogenous ligand(s) and the molecular mechanism of ligand access to the binding site, have not yet been unequivocally determined. In this work, we performed molecular dynamics (MD) simulations to help clarify the potential route of access of ligand(s) to the σ1-R binding site, on which discordant results had been reported in the literature. Further, we combined computational and experimental procedures (i.e., virtual screening (VS), electron density map fitting and fluorescence titration experiments) to provide indications about the nature of σ1-R endogenous ligand(s). Our MD simulations on human σ1-R suggested that ligands access the binding site through a cavity that opens on the protein surface in contact with the membrane, in agreement with previous experimental studies on σ1-R from Xenopus laevis. Additionally, steroids were found to be among the preferred σ1-R ligands predicted by VS, and 16,17-didehydroprogesterone was shown by fluorescence titration to bind human σ1-R, with significantly higher affinity than the prototypic σ1-R ligand pridopidine in the same essay. These results support the hypothesis that steroids are among the most important physiological σ1-R ligands.
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Project description:Humans and many animals show 'freezing' behavior in response to threatening stimuli. In humans, inappropriate threat responses are fundamental characteristics of several mental illnesses. To identify small molecules that modulate threat responses, we developed a high-throughput behavioral assay in zebrafish (Danio rerio) and evaluated 10,000 compounds for their effects on freezing behavior. We found three classes of compounds that switch the threat response from freezing to escape-like behavior. We then screened these for binding activity across 45 candidate targets. Using target profile clustering, we identified the sigma-1 (σ1) receptor as having a role in the mechanism of behavioral switching and confirmed that known σ1 ligands also disrupt freezing behavior. Furthermore, mutation of the gene encoding σ1 prevented the behavioral effect of escape-inducing compounds. One compound, which we call finazine, potently bound mammalian σ1 and altered threat-response behavior in mice. Thus, pharmacological and genetic interrogation of the freezing response revealed σ1 as a mediator of threat responses in vertebrates.
| S-EPMC4912403 | biostudies-literature
Project description:The α4β2 nAChR is implicated in a range of diseases and disorders including nicotine addiction, epilepsy and Parkinson's and Alzheimer's diseases. Designing α4β2 nAChR selective inhibitors could help define the role of the α4β2 nAChR in such disease states. In this study, we aimed to modify globular and ribbon α-conotoxin GID to selectively target the α4β2 nAChR through competitive inhibition of the α4(+)β2(-) or α4(+)α4(-) interfaces. The binding modes of the globular α-conotoxin [γ4E]GID with rat α3β2, α4β2 and α7 nAChRs were deduced using computational methods and were validated using published experimental data. The binding mode of globular [γ4E]GID at α4β2 nAChR can explain the experimental mutagenesis data, suggesting that it could be used to design GID variants. The predicted mutational energy results showed that globular [γ4E]GID is optimal for binding to α4β2 nAChR and its activity could not likely be further improved through amino-acid substitutions. The binding mode of ribbon GID with the (α4)3(β2)2 nAChR was deduced using the information from the cryo-electron structure of (α4)3(β2)2 nAChR and the binding mode of ribbon AuIB. The program FoldX predicted the mutational energies of ribbon [γ4E]GID at the α4(+)α4(-) interface, and several ribbon[γ4E]GID mutants were suggested to have desirable properties to inhibit (α4)3(β2)2 nAChR.
| S-EPMC8469569 | biostudies-literature
Project description:Nicotine improves cognitive performance and attention in both experimental animals and in human subjects, including patients affected by neuropsychiatric disorders. However, the specific molecular mechanisms underlying nicotine-induced behavioral changes remain unclear. We have recently shown in mice that repeated injections of nicotine, which achieve plasma concentrations comparable to those reported in high cigarette smokers, result in an epigenetically induced increase of glutamic acid decarboxylase 67 (GAD(67)) expression. Here we explored the impact of synthetic α(4)β(2) and α(7) nAChR agonists on GABAergic epigenetic parameters. Varenicline (VAR), a high-affinity partial agonist at α(4)β(2) and a lower affinity full agonist at α(7) neuronal nAChR, injected in doses of 1-5 mg/kg/s.c. twice daily for 5 days, elicited a 30-40% decrease of cortical DNA methyltransferase (DNMT)1 mRNA and an increased expression of GAD(67) mRNA and protein. This upregulation of GAD(67) was abolished by the nAChR antagonist mecamylamine. Furthermore, the level of MeCP(2) binding to GAD(67) promoters was significantly reduced following VAR administration. This effect was abolished when VAR was administered with mecamylamine. Similar effects on cortical DNMT1 and GAD(67) expression were obtained after administration of A-85380, an agonist that binds to α(4)β(2) but has negligible affinity for α(3)β(4) or α(7) subtypes containing nAChR. In contrast, PNU-282987, an agonist of the homomeric α(7) nAChR, failed to decrease cortical DNMT1 mRNA or to induce GAD(67) expression. The present study suggests that the α(4)β(2) nAChR agonists may be better suited to control the epigenetic alterations of GABAergic neurons in schizophrenia than the α(7) nAChR agonists.
| S-EPMC3096806 | biostudies-literature