Alexandros Makriyannis's research while affiliated with Northeastern University and other places

Publications (518)

Article
The endocannabinoid system of the gastrointestinal tract is involved in the control of intestinal barrier function. Whether the cannabinoid 1 (CB1) receptor is expressed on the intestinal epithelium and acutely regulates barrier function has not been determined. Here we tested the hypothesis that ligands of the CB1 receptor acutely modulate small i...
Preprint
Painful peripheral neuropathy is the most common neurological complication associated with human immune deficiency virus (HIV) infection. Currently available treatments fail to provide adequate symptom relief, indicating the need for novel treatment strategies. To address this gap in knowledge, we characterized the impact of cannabinoid CB2 agonist...
Article
Human endocannabinoid signaling is primarily mediated by the G-protein coupled receptors CB1 and CB2. These receptors have been linked to a variety of physiological processes and are being pursued as prospective drug candidates because of their potential to treat pain and inflammation. Due to their high sequence homology, as well as similarity in a...
Article
Extensive evidence suggests the existence of a functional interaction between endogenous cannabinoids and opioid systems. Targeting cannabinoid CB1 receptors might be a promising approach for developing new medications for opioid addiction. The present studies were undertaken to evaluate the effects of CB1 agonists and antagonists in rats (n=8) tra...
Article
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While the prevalence of breast cancer metastasis in the brain is significantly higher in triple negative breast cancers (TNBCs), there is a lack of novel and/or improved therapies for these patients. Monoacylglycerol lipase (MAGL) is a hydrolase involved in lipid metabolism that catalyzes the degradation of 2-arachidonoylglycerol (2-AG) linked to g...
Article
Hexavalent chromium [Cr(VI)] pollution is a serious environmental problem, due to not only its toxicity but also carcinogenesis. Although studies reveal several features of Cr(VI)-induced carcinogenesis, the underlying mechanisms of how Cr(VI) orchestrates multiple mitogenic pathways to promote tumor initiation and progression remain not fully unde...
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Structure-based virtual ligand screening is emerging as a key paradigm for early drug discovery owing to the availability of high-resolution target structures1–4 and ultra-large libraries of virtual compounds5,6. However, to keep pace with the rapid growth of virtual libraries, such as readily available for synthesis (REAL) combinatorial libraries⁷...
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Introduction: Cannabis acceptance and use continues to rise despite the gaps in knowledge regarding the mechanisms of cannabinoids and the endocannabinoid system in many physiological functions, including respiratory influence. Methods: With recent evidence of cannabinoid receptor 1 (CB1R) presence in the collection of respiratory neurons in the br...
Article
2-Arachidonoylglycerol (2-AG) is the most potent and abundant endocannabinoid that acts as a full agonist at the cannabinoid 1 (CB1) and 2 (CB2) receptors. It serves as a substrate for several serine hydrolases, including monoacylglycerol lipase (MGL), α/β hydrolase domain 6 (ABHD6) and fatty acid amide hydrolase (FAAH). However, 2-AG's rapid conve...
Article
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In earlier work, we explored the SAR for the C3 side chain pharmacophore in the hexahydrocannabinol template represented by the drug nabilone, which resulted in the development of AM2389. In an effort for further optimization, we have merged features of nabilone and AM2389 and explored the C3 side chain with varying chain lengths and terminal subst...
Article
Background and Purpose N-acylethanolamine acid amidase (NAAA) is a lysosomal enzyme accountable for the breakdown of N-acylethanolamides (NAEs) and its pharmacological inhibition determines beneficial effects in inflammatory conditions. The knowledge of NAAA in cancer is fragmentary with an unclarified mechanism whereas its contribution to colorect...
Preprint
Full-text available
While the prevalence of breast cancer metastasis in the brain is significantly higher in triple negative breast cancers (TNBCs), there is a lack of novel and/or improved therapies for these patients. Monoacylglycerol lipase (MAGL) is a hydrolase involved in lipid metabolism that catalyzes the degradation of 2-arachidonoylglycerol (2-AG) linked to g...
Article
The transient receptor potential (TRP) superfamily of cation channels, of which the TRP vanilloid type 1 (TRPV1) receptor plays a critical role in inflammatory and neuropathic pain, is expressed on nociceptors and spinal cord dorsal horn neurons. TRPV1 is also expressed on spinal astrocytes and dorsal root ganglia (DRG) satellite cells. Agonists of...
Article
Due to the lack of genetically encoded probes for fluorine-19 nuclear magnetic resonance spectroscopy (19F NMR), its utility for probing eukaryotic membrane protein dynamics is limited. Here we report an efficient method for the genetic incorporation of an unnatural amino acid (UAA), 3'-trifluoromenthyl-phenylalanine (mtfF), into cannabinoid recept...
Article
CB2 cannabinoid receptors (CB2) are a promising therapeutic target that lacks unwanted side effects of CB1 activation. However, the cell types expressing CB2 that mediate these effects remain poorly understood. We used transgenic mice with CB2 promoter-driven expression of enhanced green fluorescent protein (EGFP) to study cell types that express C...
Article
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Opioids are essential drugs for pain management, although long-term use is accompanied by tolerance, necessitating dose escalation, and dependence. Pharmacological treatments that enhance opioid analgesic effects and/or attenuate the development of tolerance (with a desirable opioid-sparing effect in treating pain) are actively sought. Among them,...
Article
Fine‐tuning than complete disruption of 2‐arachidonoylglycerol (2‐AG) metabolism in the brain represents a promising pharmacological approach to limit potential untoward effects associated with complete blockade of monoacylglycerol lipase (MGL), the primary hydrolase of 2‐AG. This could be achieved through a/b‐hydrolase domain containing 6 (ABHD6)...
Article
N-acylethanolamines (NAEs) are endogenous bioactive lipids reported to exert anti-inflammatory and neuroprotective effects mediated by cannabinoid receptors and peroxisome proliferator–activated receptors (PPARs), among others. Therefore, interfering with NAE signaling could be a promising strategy to decrease inflammation in neurological disorders...
Article
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Article
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N-Acylethanolamines are signaling lipid molecules implicated in pathophysiological conditions associated with inflammation and pain. N-Acylethanolamine acid amidase (NAAA) favorably hydrolyzes lipid palmitoylethanolamide, which plays a key role in the regulation of inflammatory and pain processes. The synthesis and structure-activity relationship s...
Poster
Background: Clinical research shows that regular use of 9-tetrahydrocannabinol (THC), a CB1 receptor partial agonist, during adolescence increases the propensity for developing psychosis in adulthood. CB1 receptor expression is abundant in the hippocampus, and its alteration might be behind the structural and functional hippocampal changes reporte...
Article
It has been established that the endogenous cannabinoid (endocannabinoid) system plays key modulatory roles in a wide variety of pathological conditions. The endocannabinoid system comprises both cannabinoid receptors, their endogenous ligands including 2-arachidonoylglycerol (2-AG), N-arachidonylethanolamine (anandamide, AEA), and enzymes that reg...
Article
We report the development of novel cannabinergic probes that can stabilize the cannabinoid receptors (CBRs) through tight binding interactions. Ligand design involves the introduction of select groups at a judiciously chosen position within the classical hexahydrocannabinol template (monofunctionalized probes). Such groups include the electrophilic...
Article
Background: Dietary long-chain polyunsaturated fatty acids are known to benefit infant development. After birth, human milk provides arachidonic, eicosapentaenoic, and docosahexaenoic acids to the infant. Endocannabinoids are endogenous lipid mediators derived from the long-chain polyunsaturated fatty acids. Although the roles and the mechanisms o...
Article
The endocannabinoid system has been shown to be a putative therapeutic target for retinal disease. Here, we aimed to investigate the ability of the endocannabinoid 2-arachidonoylglycerol (2-AG) and novel inhibitors of its metabolic enzymes, α/β-hydrolase domain-containing 6 (ABHD6) and monoacylglycerol lipase (MAGL), a) to protect the retina agains...
Article
Background Although paclitaxel is an effective chemotherapeutic agent used to treat multiple types of cancer (e.g., breast, ovarian, neck, and lung), it also elicits paclitaxel‐induced peripheral neuropathy (PIPN), which represents a major dose‐limiting side effect of this drug. Methods As the endogenously produced N‐acylethanolamine, palmitoyleth...
Article
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The role of cannabinoid receptors in nephropathy is gaining much attention. This study investigated the effects of two neutral CB1 receptor antagonists, AM6545 and AM4113, on nephropathy associated with metabolic syndrome (MetS). MetS was induced in rats by high-fructose high-salt feeding for 12 weeks. AM6545, the peripheral silent antagonist and A...
Article
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As a continuation of earlier work on classical cannabinoids bearing bulky side chains we report here the design, synthesis, and biological evaluation of 3'-functionalized oxa-adamantyl cannabinoids as a novel class of cannabinergic ligands. Key synthetic steps involve nucleophilic addition/transannular cyclization of aryllithium to epoxyketone in t...
Chapter
Cannabis sativa spp. is an exceptional multicomponent natural resource used as nutritional supplements, textiles, building materials, body care products, food, and medicines, to name a few. It has been cultivated for millennia to exploit the plant’s toolbox of useful natural compounds it offers. This chapter explores the chemical constituents respo...
Article
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Introduction: An escalating number of fatalities resulting from accidental opioid overdoses typically attributed to respiratory depression continue to define the opioid epidemic. Opioid respiratory depression results from a decrease in reflexive inspiration within the preBö tzinger complex in the brainstem. Objective: Cannabinoid receptor agonism i...
Article
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The CB2 R agonist AM1710, examined in animal models of peripheral neuropathy, is effective in controlling aberrant light touch sensitivity, referred to as mechanical allodynia. However, nonspecific binding of AM1710 to CB1 R, either peripherally or centrally, could be partially responsible for the analgesic effects of AM1710. Thus, we sought to det...
Chapter
The endocannabinoid system is a complex network of lipids, G protein-coupled receptors (GPCRs), and metabolic enzymes and plays a major role in modulating key physiological processes, including nociception, inflammation, and metabolism. The type-1 cannabinoid receptor (CB1) holds great promise for treating CNS and metabolic disorders, pain and glau...
Article
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Inhibition of human Monoacylglycerol Lipase (hMGL) offers a novel approach for treating neurological diseases. The design of inhibitors, targeting active-inactive conformational transitions of the enzyme, can be aided by understanding the interplay between structure and dynamics. Here, we report the effects of mutations within the catalytic triad o...
Article
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Background and Objectives: Insulin resistance (IR) is a serious condition leading to development of diabetes and cardiovascular complications. Hyper-activation of cannabinoid receptors-1 (CB1) has been linked to the development of metabolic disorders such as IR. Therefore, the effect of blocking CB1 on the development of IR was investigated in the...
Article
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Objective: The endocannabinoid (eCB) system is increasingly recognized as being of crucial importance in obesity-related hepatic steatosis. eCBs, via activation of the hepatic cannabinoid-1 receptor (CB1R), modulate lipogenesis and fatty acid oxidation. However, the underlying molecular mechanisms are largely unknown. Methods: We combined unbias...
Article
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Adamantyl groups are key structural subunit commonly used in many marketed drugs targeting diseases ranging from viral infections to neurological disorders. The metabolic disposition of adamantyl compounds has been mostly studied using LC-MS based approaches. However, metabolite quantities isolated from biological preparations are often insufficien...
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Attenuating emesis elicited by both disease and medical treatments of disease remains a critical public health challenge. Although cannabinergic medications have been used in certain treatment-resistant populations, FDA-approved cannabinoid antiemetics are associated with undesirable side effects, including cognitive disruption, that limit their pr...
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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A new approach to synthesize cannabilactones using Suzuki cross-coupling reaction followed by one-step demethylation-cyclization is presented. The two key cannabilactone prototypes AM1710 and AM1714 were obtained selectively in high overall yields and in a lesser number of synthetic steps when compared to our earlier synthesis. The new approach exp...
Article
Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, and lack of activation and G protein-coupling knowledge have hindered the development of therapeutic applications. Importantly, missing structural inform...
Article
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The current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens1,2. These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds3,4. As a result, the last class of antibiotics acting against Gram-negative bacteria was developed in the 1960s². We reason that...
Article
N-acylethanolamine acid amidase (NAAA) inhibition represents an exciting novel approach to treat inflammation and pain. NAAA is a cysteine amidase which preferentially hydrolyzes the endogenous biolipids palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). PEA is an endogenous agonist of the nuclear peroxisome proliferator-activated receptor-α...
Article
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Despite a growing acceptance that withdrawal symptoms can emerge following discontinuation of cannabis products, especially in high intake chronic users, there are no FDA-approved treatment options. Drug development has been hampered by difficulties studying cannabis withdrawal in laboratory animals. One preclinical approach that has been effective...
Article
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In earlier work, we reported a novel class of CB2 selective ligands namely cannabilactones. These compounds carry a dimethylheptyl substituent at C3, which is typical for synthetic cannabinoids. In the current study with the focus on the pharmacophoric side chain at C3 we explored the effect of replacing the C1-gem-dimethyl group with the bulkier c...
Article
Cannabinoid receptor 1 (CB1) is a potential therapeutic target for the treatment of pain, obesity and obesity-related metabolic disorders, and addiction. The crystal structure of human CB1 has been determined in complex with the stabilizing antagonist AM6538. In the present study, we characterize AM6538 as a tight-binding/irreversible antagonist of...
Article
Background and purpose The morbidity and mortality associated with recreational use of synthetic cannabinoid receptor agonists (SCRAs) may reflect strong activation of CB1 receptors and is a major health concern. The properties of SCRA at CB1 are not well defined, so we sought to develop an assay to determine acute CB1 efficacy using receptor deple...
Article
Background and Purpose Delta-9-tetrahydrocannabinol (THC) acts via cannabinoid 1 receptors (CB1Rs) to increase feeding. Here, we assessed the orexigenic effect of AM11101, a novel CB1R agonist designed to have a more favorable pharmacodynamic profile than THC. Experimental Approach The acute, orexigenic effects of AM11101 and THC were compared in...
Article
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Gut-brain signaling controls feeding behavior and energy homeostasis; however, the underlying molecular mechanisms and impact of diet-induced obesity (DIO) on these pathways are poorly defined. We tested the hypothesis that elevated endocannabinoid activity at cannabinoid CB1 receptor (CB1Rs) in the gut of mice rendered DIO by chronic access to a h...
Article
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Approximately 20 million adults in the United States have an alcohol use disorder. In recent years, modulation of the behavioral effects of ethanol by phytochemicals has been explored. In this study, we used the ethanol-induced loss of righting reflex (LORR) assay to assess potency differences between the sesquiterpene phytochemical beta-caryophyll...
Chapter
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The use of cannabis for animal species is an area of growing interest, largely due to the therapeutic benefits being observed for humans and animals in the era of cannabis legalization. The close relationship humans have with their pets and other veterinary species has led to a renewed interest in the possibility and promise of cannabis to treat si...
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Rationale Lower lip retraction (LLR) in rats has been described as a distinctive effect of 5-HT1A agonists. In the course of evaluating behavioral effects of cannabinoid agonists in rats, LLR effects were evident following injection of several cannabinoid agonists. Objectives To pharmacologically characterize cannabinoid-induced LLR in rats. Meth...
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Background Recognized as the gold-standard ideal fare, human milk has a unique composition that meets infants’ needs throughout development. Endocannabinoids and endocannabinoid-like compounds [endocannabinoid metabolome (ECM)] are endogenous lipid mediators derived from long-chain polyunsaturated fatty acids. Based on animal models, it has been pr...
Article
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Human alpha/beta hydrolase domain 6 (hABHD6) is an enzyme that hydrolyzes 2-arachidonoylglycerol (2-AG), a potent agonist at both cannabinoid CB1 and CB2 receptors. In vivo modulation of ABHD6 expression has been shown to have potential therapeutic applications, making the enzyme a promising drug target. However, the lack of structural information...