Ensemble-Based Virtual Screening for Cannabinoid-Like Potentiators of the Human Glycine Receptor α1 for the Treatment of Pain
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The human glycine receptors (hGlyRs) are chloride-selective ion channels that mediate inhibitory neurotransmission in the brain stem and spinal cord. They are also targets for compounds of potential use in analgesic therapies. Here, we develop a strategy to discover analgesic drugs via structure-based virtual screening based on the recently published NMR structure of the hGlyR-α1 transmembrane domain (PDB ID: 2M6I) and the critical role of residue S296 in hGlyR-α1 potentiation by Δ9-tetrahydrocannabinol (THC). We screened 1549 FDA-approved drugs in the DrugBank database on an ensemble of 180 hGlyR-α1 structures generated from molecular dynamics simulations of the NMR structure of the hGlyR-α1 transmembrane domain in different lipid environments. Thirteen hit compounds from the screening were selected for functional validation in Xenopus laevis oocytes expressing hGlyR-α1. Only one compound showed no potentiation effects; seven potentiated hGlyR-α1 at a level greater than THC at 1 μM. Our virtual screening protocol is generally applicable to drug targets with lipid-facing binding sites.Keywords:
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The human body possesses specific binding sites on the surface of many cell types for cannabinoids, and our body produces several endocannabinoids, fatty acid derivatives that bind to these cannabinoid receptors (CB) and activate them. CB receptors and endocannabinoids together constitute the endocannabinoid system. Some phytocannabinoids, cannabinoids of the cannabis plant, and a multitude of synthetic cannabinoids produced in the laboratory mimic the effects of endocannabinoids. ∆ 9 -THC (dronabinol), the pharmacologically most active cannabinoid of the cannabis plant, binds to both types of cannabinoid receptors that have been identified so far, the CB1 and the CB2 receptor. These receptors have been found in the central nervous system (brain and spinal cord) and many peripheral tissues and organs. Depending on the kind of cells, on dose and state of the body, activation of CB receptors may cause a multitude of effects including euphoria, anxiety, dry mouth, muscle relaxation, hunger and pain reduction. Besides activation of CB receptors several other approaches are under investigation to influence the cannabinoid system with therapeutic intent, including blockade of CB receptors (antagonism) and modulation of endocannabinoid concentrations by inhibition of their degradation. Currently, several preparations that stimulate cannabinoid receptors (dronabinol, nabilone and cannabis) and one compound that blocks the CB1 receptor (rimonabant) are used medicinally.
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The discovery of cannabinoid receptors, together with the development of selective cannabinoid receptor antagonists, has encouraged a resurgence of cannabinoid pharmacology. With the identification of endogenous agonists, such as anandamide, scientists have sought to uncover the biological role of endocannabinoid systems; initially guided by the long-established actions of cannabis and exogenous cannabinoids such as Δ9-tetrahydrocannabinol (THC). In particular, considerable research has examined endocannabinoid involvement in appetite, eating behaviour and body weight regulation. It is now confirmed that endocannabinoids, acting at brain CB1 cannabinoid receptors, stimulate appetite and ingestive behaviours, partly through interactions with more established orexigenic and anorexigenic signals. Key structures such as the nucleus accumbens and hypothalamic nuclei are sensitive sites for the hyperphagic actions of these substances, and endocannabinoid activity in these regions varies in relation to nutritional status and feeding expression. Behavioural studies indicate that endocannabinoids increase eating motivation by enhancing the incentive salience and hedonic evaluation of ingesta. Moreover, there is strong evidence of an endocannabinoid role in energy metabolism and fuel storage. Recent developments point to potential clinical benefits of cannabinoid receptor antagonists in the management of obesity, and of agonists in the treatment of other disorders of eating and body weight regulation.
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▪ Abstract CB1 and CB2 cannabinoid receptors are the primary targets of endogenous cannabinoids (endocannabinoids). These G protein–coupled receptors play an important role in many processes, including metabolic regulation, craving, pain, anxiety, bone growth, and immune function. Cannabinoid receptors can be engaged directly by agonists or antagonists, or indirectly by manipulating endocannabinoid metabolism. In the past several years, it has become apparent from preclinical studies that therapies either directly or indirectly influencing cannabinoid receptors might be clinically useful. This review considers the components of the endocannabinoid system and discusses some of the most promising endocannabinoid-based therapies.
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This review evaluates the cellular mechanisms of constitutive activity of the cannabinoid (CB) receptors, its reversal by inverse agonists, and discusses the pitfalls and problems in the interpretation of the research data. The notion is presented that endogenously produced anandamide (AEA) and 2-arachidonoylglycerol (2-AG) serve as autocrine or paracrine stimulators of the CB receptors, giving the appearance of constitutive activity. It is proposed that one cannot interpret inverse agonist studies without inference to the receptors' environment vis-à-vis the endocannabinoid agonists which themselves are highly lipophilic compounds with a preference for membranes. The endocannabinoid tone is governed by a combination of synthetic pathways and inactivation involving transport and degradation. The synthesis and degradation of 2-AG is well characterized, and 2-AG has been strongly implicated in retrograde signalling in neurons. Data implicating endocannabinoids in paracrine regulation have been described. Endocannabinoid ligands can traverse the cell's interior and potentially be stored on fatty acid-binding proteins (FABPs). Molecular modelling predicts that the endocannabinoids derived from membrane phospholipids can laterally diffuse to enter the CB receptor from the lipid bilayer. Considering that endocannabinoid signalling to CB receptors is a much more likely scenario than is receptor activation in the absence of agonist ligands, researchers are advised to refrain from assuming constitutive activity except for experimental models known to be devoid of endocannabinoid ligands.
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