Mary E Abood

Mary E Abood
Temple University | TU · Center for Substance Abuse Research (CSAR)

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148
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Introduction
Skills and Expertise

Publications

Publications (148)
Article
Background: Activation of signaling effectors by G-protein coupled receptors (GPCRs) depends on different molecular mechanisms triggered by conserved amino acid residues. Although studies have focused on the G-protein signaling state, the mechanism for β-arrestin signaling by CB1 is not yet well defined. Studies have indicated that transmembrane he...
Article
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KLS-13019, a novel devised cannabinoid-like compound, was explored for anti-inflammatory actions in dorsal root ganglion cultures relevant to chemotherapy-induced peripheral neuropathy (CIPN). Time course studies with 3 µM paclitaxel indicated > 1.9-fold increases in immunoreactive (IR) area for cell body GPR55 after 30 min as determined by high co...
Article
The brain mechanism of inflammatory pain is an understudied area of research, particularly concerning the descending pain modulatory system. The G protein-coupled receptor 55 (GPR55) is a lysophosphatidylinositol-sensitive receptor that has also been involved in cannabinoid signaling. It is widely expressed throughout the central nervous system, in...
Article
Plant-based, synthetic, and endogenous cannabinoids have been shown to control a diverse array of biological processes, including regulation of cell fate across cancers. Their promise as broad-based antitumor agents in preclinical models has led to the initiation of pilot clinical trials. Session 5 of the National Cancer Institute’s Cannabis, Canna...
Article
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The CB1 cannabinoid receptor is a G-protein coupled receptor highly expressed throughout the central nervous system that is a promising target for the treatment of various disorders, including anxiety, pain, and neurodegeneration. Despite the wide therapeutic potential of CB1, the development of drug candidates is hindered by adverse effects, rapid...
Article
We apply the magic methyl effect to improve the potency/efficacy of GAT211, the prototypic 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator (ago-PAM). Introducing a methyl group at the α-position of nitro group generated two diastereomers, the greater potency and efficacy of erythro, (±)-9 vs threo, (±)-...
Article
There is a clear need for novel and improved therapeutic strategies for alleviating chronic neuropathic pain, as well as a need for better understanding of brain mechanisms of neuropathic pain, which are less understood than spinal and peripheral mechanisms. The G protein-coupled receptor 55 (GPR55), is a lysophosphatidylinositol (LPI)-sensitive re...
Article
GPR18 is a G protein-coupled receptor that belongs to the orphan class A family. Even though it shares low sequence homology with the cannabinoid receptors, CB1R and CB2R, a growing body of research suggests its relationship with the endocannabinoid system, not only because it is able to recognize cannabinoid ligands, but also because of its expres...
Article
Cannabinoid 1 receptor (CB1R) allosteric ligands hold far-reaching therapeutic promise. We report application of fluoro- and nitrogen-walk approaches to enhance the drug-like properties of GAT211, a prototype CB1R allosteric agonist-positive allosteric modulator (ago-PAM). Several analogs exhibited improved functional potency (cAMP, arrestin2), me...
Article
Background: Cocaine has a variety of negative effects on the central nervous system, including reports of decreased barrier function of brain microvascular endothelial cells. However, few studies have directly shown the effects of cocaine on blood-brain barrier (BBB) function in vivo. The miniature integrated fluorescence microscope (i.e., minisco...
Article
Cannabinoid receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Cannabinoid Receptors [107]) are activated by endogenous ligands that include N-arachidonoylethanolamine (anandamide), N-homo-γ-linolenoylethanolamine, N-docosatetra-7,10,13,16-enoylethanolamine and 2-arachidonoylglycerol. Potency determinations of endogenous agonists at...
Article
Full-text available
Docking studies of identified GPR55 ligands using a GPR55 inactive state model allow rationalizing key structural features involved in ligand–receptor binding. On this molecular basis, we have designed novel quinolone sulfonamide derivatives with optimized potency and efficacy. These novel molecules compounds are being synthesized and evaluated usi...
Article
GPR55, an atypical cannabinoid receptor activated by lysophosphatidylinositol (LPI) has been involved in various physiological and pathological processes. We examined the effect of GPR55 activation on rat brain microvascular endothelial cells (RBMVEC), an essential component of the blood-brain barrier (BBB). GPR55 was detected in RBMVEC by western...
Article
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Sigma-1 receptors (Sig-1Rs) are integral ER membrane proteins. They bind diverse ligands, including psychoactive drugs, and regulate many signaling proteins, including the inositol 1,4,5-trisphosphate receptors (IP3Rs) that release Ca²⁺ from the ER. The endogenous ligands of Sig-1Rs are unknown. Phospholipase D (PLD) cleaves phosphatidylcholine to...
Article
Platelet-activating factor (PAF) is a potent phospholipid mediator that exerts various pathophysiological effects by interacting with a G protein-coupled receptor. PAF has been reported to increase the permeability of the blood-brain barrier (BBB) via incompletely characterized mechanisms. We investigated the effect of PAF on rat brain microvascula...
Article
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Post-traumatic headache is the most common symptom of postconcussion syndrome and becomes a chronic neurological disorder in a substantial proportion of patients. This review provides a brief overview of the epidemiology of postconcussion headache, research models used to study this disorder, as well as the proposed mechanisms. An objective of this...
Article
Full-text available
In this work, we explored the molecular framework of the known CB1R allosteric modulator PSNCBAM-1 with the aim to generate new bioactive analogs and to deepen the structure-activity relationships of this type of compounds. In particular, the introduction of a NH group between the pyridine ring and the phenyl nucleus generated the amino-phenyl-urea...
Article
Bradykinin (BK), a component of the kallikrein-kininogen-kinin system exerts multiple effects via B1 and B2 receptor activation. In the cardiovascular system, bradykinin has cardioprotective and vasodilator properties. We investigated the effect of BK on cardiac-projecting neurons of nucleus ambiguus, a key site for the parasympathetic cardiac regu...
Chapter
With the approach of the 30th year since the pioneering discovery of a cannabinoid receptor in rat brain (Devane et al., 1988), the field of cannabinoid pharmacology and physiology has impacted human physiology at multiple levels. The development of highly specific and potent orthosteric ligands, as well as the blossoming field of allosteric ligand...
Article
Interest in lipoamino acids as endogenous modulators of G-protein coupled receptors has escalated due to their involvement in a variety of physiologic processes. In particular, a role for these amino acid conjugates has emerged in the endocannabinoid system. The study presented herein investigated the effects of N-arachidonoyl glycine (NAGly) on a...
Chapter
The CB1 and CB2 cannabinoid receptors (CB1R, CB2R) are members of the G protein-coupled receptor (GPCR) family that were identified over 20 years ago. CB1Rs and CB2Rs mediate the effects of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the principal psychoactive constituent of marijuana, and subsequently identified endogenous cannabinoids (endocannabinoids) an...
Article
Background HIV-1 infection and drug abuse are frequently co-morbid and their association greatly increases the severity of HIV-1-induced neuropathology. While nucleus accumbens (NAcc) function is severely perturbed by drugs of abuse, little is known about how HIV-1 infection affects NAcc. Methods We used calcium and voltage imaging to investigate...
Article
GPR55, a G protein-coupled receptor, is an attractive target to alleviate inflammatory and neuropathic pain and treat osteoporosis and cancer. Identifying a potent and selective ligand will aid to further establish the specific physiological roles and pharmacology of the receptor. Towards this goal, a targeted library of 22 compounds was synthesize...
Article
The pituitary adenylyl cyclase-activating polypeptide (PACAP) and its G protein-coupled receptors, PAC1, VPAC1 and VPAC2 form a system involved in a variety of biological processes. Although some sympathetic stimulatory effects of this system have been reported, its central cardiovascular regulatory properties are poorly characterized. VPAC1 recept...
Article
GPR55 is a newly de-orphanized Class A GPCR that has been implicated in inflammatory pain, neuropathic pain, metabolic disorder, bone development, and cancer. Few potent GPR55 ligands have been identified to date. This is largely due to an absence of information about salient features of GPR55, such as residues important for signaling and residues...
Article
Brain microvascular endothelial cells are a critical component of the blood-brain barrier. They form a tight monolayer which is essential for maintaining the brain homeostasis. Blood-derived proteases such as thrombin may enter the brain during pathological conditions like trauma, stroke, and inflammation and further disrupts the permeability of th...
Article
The first structure-activity relationships for a benzothiazole scaffold acting as an antagonist at GPR35 is presented. Analogues were designed based on a lead compound that was previously determined to have selective activity as a GPR35 antagonist. The synthetic route was modular in nature to independently explore the role of the middle and both en...
Article
Full-text available
Allosteric modulation of cannabinoid type-1 receptors (CB1) is a novel means through which signaling bias may be exerted. Org27569 remains the most-characterized CB1 allosteric modulator yet there are conflicting reports regarding its effects on extracellular signal-regulated kinase (ERK) signaling. We conducted a systematic evaluation of Org27569...
Article
A series of oxadiazole derivatives is prepared and tested for activity as antagonists at GPR55 in cellular beta-arrestin redistribution assays.
Article
Allosteric modulators of the cannabinoid CB1 receptor were first discovered in 2005. Since then, although both negative and positive allosteric modulators have been uncovered, many questions remain about their site(s) of action, as well as the basis of their signaling. The described covalent probe with improved potency and efficacy will facilitate...
Article
Full-text available
Sigma-1 receptor (Sig-1R) is an intracellular chaperone protein with many ligands, located at the endoplasmic reticulum. Binding of cocaine to Sig-1R has previously been found to modulate endothelial function. In the present study, we show that cocaine dramatically inhibits store-operated Ca(2+) entry (SOCE), a Ca(2+) influx mechanism promoted by d...
Patent
Full-text available
Compounds are provided having agonistic activity against G protein-coupled receptor 35 (GPR35). The compounds are useful for providing antinociception, providing neuroprotection in case of stroke or ischemia, or treating gastric inflammation.
Article
Full-text available
Emerging evidence indicates the involvement of GPR55 and its proposed endogenous ligand, lysophosphatidylinositol (LPI), in nociception, yet their role at central pain processing has not been explored. Using Ca(2+) imaging, we show here that LPI elicits concentration-dependent and GPR55-mediated increases in intracellular Ca(2+) levels in dissociat...
Article
Cocaine promotes addictive behavior primarily by blocking the dopamine transporter, thus increasing dopamine transmission in the nucleus accumbens (nAcc); however, additional mechanisms are continually emerging. Sigma-1 receptors (σ1Rs) are known targets for cocaine, yet the mechanisms underlying σ1R-mediated effects of cocaine are incompletely und...
Article
Opioids are among the most effective and commonly used analgesics in clinical practice for severe pain. However, the use of opioid medications is clinically limited by several adverse properties including dependence. While opioid dependence is a complex health condition, the treatment of HIV-infected individuals with opioid dependence presents addi...
Article
5-Lipoxygenase (5-LO) is a protein widely distributed in the central nervous system where it modulates amyloidosis and memory impairments in transgenic mouse models of Alzheimer's disease. However, no data are available as to whether 5-LO is elevated in human tauopathy or if it directly influences tau pathology in a relevant model of the disease. W...
Article
G protein-coupled estrogen receptor (GPER) is a relatively recently identified non-nuclear estrogen receptor, expressed in several tissues, including brain and blood vessels. The mechanisms elicited by GPER activation in brain microvascular endothelial cells are incompletely understood. The purpose of this work was to assess the effects of GPER act...
Article
Full-text available
The research presented details the creation of an activated state model of the putative cannabinoid receptor, GPR55, based on the crystal structure of CXCR4, a receptor with which GPR55 has high homology. Into this model, analogs of the high throughput screen compound hit, (E)-3-(2-methoxyphenyl)-N-((4-(N-methyl-N-phenylsulfamoyl)phenyl) carbamothi...
Article
Full-text available
Four-domain voltage-gated Ca(2+) and Na(+) channels (CaV, NaV) underpin nervous system function and likely emerged upon intragenic duplication of a primordial two-domain precursor. To investigate if two-pore channels (TPCs) may represent an intermediate in this evolutionary transition, we performed molecular docking simulations with a homology mode...
Article
We have recently identified 1,8-naphthyridin-2(1H)-on-3-carboxamide as a new scaffold very suitable for the development of new CB2 receptor potent and selective ligands. In this paper we describe a number of additional derivatives in which the same central scaffold has been variously functionalized in position 1 or 6. All new compounds showed high...
Article
Full-text available
The two-pore channels (TPC1 and TPC2) belong to an ancient family of intracellular ion channels expressed in the endolysosomal system. Little is known about how regulatory inputs converge to modulate TPC activity, and proposed activation mechanisms are controversial. Here, we compiled a proteomic characterization of the human TPC interactome, which...
Article
Although the initial events of Alzheimer's disease (AD) are still not known, it is clear that the disease in its sporadic form results from the combination of genetic and environmental risk factors. Among the latter, behavioral stress has been increasingly recognized as an important factor in the propagation of AD. However, the mechanisms underlyin...
Article
The therapeutic and psychoactive properties of cannabinoids have long been recognized. The type 2 receptor for cannabinoids (CB2) has emerged as an important therapeutic target in several pathologies, as it mediates beneficial effects of cannabinoids, while having little, if any psychotropic activity. Difficulties in the development of CB2-based th...
Article
Full-text available
Background and purpose: GPR18 is a candidate cannabinoid receptor, but its classification as such is controversial. The rationale of the study presented herein was to consider the effects of N-arachidonoyl glycine (NAGly) and cannabinoids via differential G-protein coupled pathways, in addition to β-arrestin signalling. Cellular localization of GP...
Article
Full-text available
The cannabinoid 1 (CB1) allosteric modulator, 5-chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-yl-phenyl)-ethyl]-amide) (ORG27569), has the paradoxical effect of increasing the equilibrium binding of [3H](-)-3-[2-hydroxyl-4-(1,1-dimethylheptyl)phenyl]-4-[3-hydroxylpropyl] cyclohexan-1-ol (CP55,940, an orthosteric agonist), while at th...
Article
Full-text available
GPR35 is a G-protein-coupled receptor expressed in the immune, gastrointestinal and nervous systems, in gastric carcinomas and is implicated in heart failure and pain perception. We investigated residues in GPR35 responsible for ligand activation and the receptor structure in the active state. GPR35 contains numerous positively charged amino acids...
Article
Recently we found that fever (part of HIV-related wasting) is induced by the action of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein (gp120) in the preoptic anterior hypothalamus (POAH). As the opioid system plays a role in the pathogenesis of HIV-1, in the present study we sought to examine the capacity of the opioid system to r...
Article
Full-text available
The L-α-lysophosphatidylinositol (LPI)-sensitive receptor GPR55 is coupled to Ca²⁺ signaling. Low levels of GPR55 expression in the heart have been reported. Similar to other G protein-coupled receptors involved in cardiac function, GPR55 may be expressed both at the sarcolemma and intracellularly. Thus, to explore the role of GPR55 in cardiomyocyt...
Article
Full-text available
Activation of the CB1 receptor is modulated by aspartate residue D2.63(176) in transmembrane helix (TMH) II. Interestingly, D2.63 does not affect the affinity for ligand binding at the CB1 receptor. Studies in class A GPCRs have suggested an ionic interaction between residues of TMHII and VII. In this report, modeling studies identified residue K37...
Chapter
For centuries the plants Cannabis sativa and Cannabis indica (commonly known as marijuana) have been used for recreational, religious, and medicinal purposes across diverse cultures. The first recorded attributes of Cannabis were on its potent therapeutic actions, which included analgesic, sedative, and anticonvulsant effects. In the 1930s Cannabis...
Book
This book is intended as a scientific resource for cannabinoid researchers carrying out animal and human experiments, and for those who are interested in learning about future directions in cannabinoid research. Additionally, this book may be of value to investigators currently working outside the field of cannabinoid research who have an interest...
Article
We have previously identified allosteric modulators of the cannabinoid CB(1) receptor (Org 27569, PSNCBAM-1) which display a contradictory pharmacological profile: increasing the specific binding of the CB(1) receptor agonist [(3)H]CP55940 but producing a decrease in CB(1) receptor agonist efficacy. Here we investigated the effect one or both compo...
Article
This review presents a summary of what is known about the G-protein coupled receptors GPR35 and GPR55 and their potential characterization as lysophospholipid or cannabinoid receptors, respectively. Both GPR35 and GPR55 have been implicated as important targets in pain and cancer, and additional diseases as well. While kynurenic acid was suggested...
Article
Full-text available
The role of cannabinoid receptors in inflammation has been the topic of many research endeavors. Despite this effort, to date the involvement of the endocannabinoid system (ECS) in inflammation remains obscure. The ambiguity of cannabinoid involvement may be explained by the existence of cannabinoid receptors, other than CB(1) and CB(2), or a conse...
Article
Full-text available
Recent studies have demonstrated that the majority of endogenous cannabinoid type 1 (CB1) receptors do not reach the cell surface but are instead associated with endosomal and lysosomal compartments. Using calcium imaging and intracellular microinjection in CB1 receptor-transfected HEK293 cells and NG108-15 neuroblastoma × glioma cells, we provide...
Article
Marijuana is the most widely abused illegal drug, and its spectrum of effects suggests that several receptors are responsible for the activity. Two cannabinoid receptor subtypes, CB1 and CB2, have been identified, but the complex pharmacological properties of exogenous cannabinoids and endocannabinoids are not fully explained by their signaling. Th...
Article
Clinical studies indicate that alcohol dependence has an additive effect on cognitive deficits associated with HIV-1 infection. Findings in humans and animal models suggest that alcohol, similar to HIV-1, induces inflammatory processes in the brain leading to neurodegeneration. The causes of HIV-1-associated neurotoxicity are comparable to those me...
Article
Both L-α-lysophosphatidylinositol (LPI) and 2-arachidonoyl-sn-glycero-3-phosphoinositol (2-AGPI) have been reported to activate the putative cannabinoid receptor, GPR55. Recent microsecond time-scale molecular dynamics (MD) simulations and isothiocyanate covalent labeling studies have suggested that a transmembrane helix 6/7 (TMH6/7) lipid pathway...
Article
Full-text available
There are at least two types of cannabinoid receptors (CB(1) and CB(2)). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ(9)-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligan...
Article
Full-text available
Known agonists of the orphan receptor GPR35 are kynurenic acid, zaprinast, 5-nitro-2-(3-phenylproplyamino) benzoic acid, and lysophosphatidic acids. Their relatively low affinities for GPR35 and prominent off-target effects at other pathways, however, diminish their utility for understanding GPR35 signaling and for identifying potential therapeutic...
Article
The Cannabis sativa plant has been exploited for medicinal, agricultural and spiritual purposes in diverse cultures over thousands of years. Cannabis has been used recreationally for its psychotropic properties, while effects such as stimulation of appetite, analgesia and anti-emesis have lead to the medicinal application of cannabis. Indeed, repor...
Article
Full-text available
Significant advances have increased our understanding of the molecular mechanisms of amyotrophic lateral sclerosis (ALS), yet this has not translated into any greatly effective therapies. It appears that a number of abnormal physiological processes occur simultaneously in this devastating disease. Ideally, a multidrug regimen, including glutamate a...
Article
GPR55 has recently attracted much attention as another member of the cannabinoid family, potentially explaining physiological effects that are non-CB1/CB2 mediated. However, the data gathered so far are conflicting with respect to its pharmacology. We review the primary literature to date on GPR55, describing its discovery, structure, pharmacology...
Article
GPR35, a recently deorphanized Class A G-protein coupled receptor, shows prominent expression in immune and gastrointestinal tissues (Wang et al. JBC, 2006), with additional expression in pancreatic islets, skeletal muscle, and lung (Horikawa et al. Nat. Genet. 2000), brain and spinal cord. An endogenous ligand of GPR35, kynurenic acid, is one of t...
Article
GPR55 is a Class A G protein-coupled receptor that has been shown to be activated by cannabinoids (Henstridge et al. FASEB J, 2008). The receptor is expressed in several mammalian tissues including several brain regions. It has been reported that GPR55 is also activated by LPI found in rat brain (Oka et al. BBRC, 2007), with 2-AGPI having the highe...
Chapter
Although many known receptors that regulate addiction have been pharmacologically and biochemically well characterized, some orphan receptors with homology to known receptors of abuse (i.e. GPR35) remain uncharacterized. GPR35 is a G-protein coupled receptor, first identified in 1998 after a screen of a human genomic library. More recent RT-PCR stu...