Kenneth A. Jacobson

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Verified

Kenneth verified their affiliation via an institutional email.

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• Ph.D.
• Chief, Molecular Recognition Section, Laboratory of Bioorganic Chemistry at National Institutes of Health

Activation of PLCβ enzymes by Giβγ and Gαq/11 proteins is a common mechanism to trigger cytosolic Ca²⁺ increase. We and others reported that Gαq/11 inhibitor FR900359 (FR) can inhibit both Gαq- and, surprisingly, Giβγ-mediated intracellular Ca²⁺ mobilization. Thus, the Gαi-Gβγ-PLCβ-Ca²⁺ signaling axis depends entirely on the presence of active Gαq,...

Various series of 4,6‐disubstituted‐2‐thiopyridine derivatives were synthesized and evaluated as potential ecto‐5’‐nucleotidase (CD73) inhibitors. Altogether, about ninety compounds were prepared using a general synthetic pathway involving one or two steps (eventually one‐pot) procedures. Variation of the nature of the substituents in positions 4 a...

Abraham Patchornik was born in 1926 in Ness Ziona, a town in Palestine founded by his great-grandfather Reuben Lehrer in 1883. He started to study chemistry as an undergraduate at the Hebrew University. However, this was interrupted by the war, and he completed his studies in various locations in West Jerusalem. From 1952 to 1956 Patchornik complet...

Incorporating photoisomerizable moieties within drugs offers the possibility of rapid and reversible light-dependent switching between active and inactive configurations. Here, we developed a photoswitchable adenosine A3 receptor (A3R) agonist that confers optical control on this G protein-coupled receptor through noninvasive topical skin irradiati...

Alterations in mitochondrial function are the linchpin in numerous disease states including in the development of chemotherapy-induced neuropathic pain (CIPN), a major dose-limiting toxicity of widely used chemotherapeutic cytotoxins. In CIPN, mitochondrial dysfunction is characterized by deficits in mitochondrial bioenergetics (e.g., decreased ATP...

Ecto-5’-nucleotidase (CD73) is a potential new drug target for cancer immunotherapy. Its overexpression is associated with various aggressive cancers, including triple-negative breast cancer (TNBC) and pancreatic cancer, making it a promising target for diagnostic imaging. Besides antibodies, small molecule CD73 inhibitors have been developed and a...

Activation of PLCβ enzymes by G iβγ and G αq/11 proteins is a common mechanism to trigger cytosolic Ca ²⁺ increase. We and others reported that G αq/11 inhibitor FR900358 (FR) can inhibit both and G αq - and, surprisingly, G iβγ -mediated intracellular Ca ²⁺ mobilization. Thus, the G αi -G βγ -PLCβ-Ca ²⁺ signaling axis depends entirely on the prese...

Metabolic incorporation of chemically tagged monosaccharides is a facile means of tagging cellular glycoproteins and glycolipids. However, since the monosaccharide precursors are often shared by several pathways, selectivity has been difficult to attain. For example, N-linked glycosylation is a chemically complex and ubiquitous posttranslational mo...

Background and Purpose Adenosine, through the A1 receptor (A1R), is an endogenous anticonvulsant. The development of adenosine receptor agonists as antiseizure medications has been hampered by their cardiac side effects. A moderately A1R‐selective agonist, MRS5474, has been reported to suppress seizures without considerable cardiac action. Hypothes...

The P2Y6 receptor (P2Y6R), a Gq-coupled receptor, is a potential drug discovery target for various inflammatory and degenerative conditions. Antagonists have been shown to attenuate colitis, acute lung injury, etc. In the search for competitive antagonists, we have investigated the SAR of 3-nitro-2-(trifluoromethyl)-2H-chromene derivatives, althoug...

The neurotransmitter dopamine has central roles in mood, appetite, arousal and movement 1. Despite its importance in brain physiology and function, and as a target for illicit and therapeutic drugs, the human dopamine transporter (hDAT) and mechanisms by which it is inhibited by small molecules and Zn 2+ are without a high-resolution structural con...

The neurotransmitter dopamine has central roles in mood, appetite, arousal and movement¹. Despite its importance in brain physiology and function, and as a target for illicit and therapeutic drugs, the human dopamine transporter (hDAT) and mechanisms by which it is inhibited by small molecules and Zn²⁺ are without a high-resolution structural conte...

Background and Purpose Adenosine, through the A1 receptor (A1R), is an endogenous anticonvulsant. Development of adenosine receptor agonists as antiseizure medications has been hampered by their cardiac side effects. A moderately A1R-selective agonist, MRS5474, has been reported to suppress seizures without considerable cardiac action. Hypothesizin...

Diverse G protein-coupled receptors (GPCRs) are expressed in different metabolic tissues and are involved in the regulation of whole-body glucose and energy homeostasis. Dysregulation of glucose homeostasis contributes to hyperglycemia in obesity and type 2 diabetes (T2D). Thus, GPCRs have emerged as important therapeutic targets for anti-obesity a...

The A2B adenosine receptor (A2BR) is one of the four adenosine-activated G protein-coupled receptors. In addition to adenosine, protein kinase C (PKC) was recently found to activate the A2BR. The A2BR is coupled to both Gs and Gi, as well as Gq proteins in some cell types. Many primary cells and cell lines, such as bladder and breast cancer, bronch...

Terpenes are small hydrocarbon compounds that impart aroma and taste to many plants, including Cannabis sativa . A number of studies have shown that terpenes can produce pain relief in various pain states in both humans and animals. However, these studies were methodologically limited and few established mechanisms of action. In our previous work,...

Adenosine receptors are a family of purinergic G protein–coupled receptors that are widely distributed in bodily organs and in the peripheral and central nervous systems. Recently, antihyperalgesic actions have been suggested for the adenosine A 3 receptor, and its agonists have been proposed as new neuropathic pain treatments. We hypothesized that...

The P2Y6 receptor, activated by uridine diphosphate (UDP), is a target for antagonists in inflammatory, neurodegenerative, and metabolic disorders, yet few potent and selective antagonists are known to date. This prompted us to use machine learning as a novel approach to aid ligand discovery, with pharmacological evaluation at three P2YR subtypes:...

The A3 adenosine receptor (AR) is an important inflammatory and immunological target. However, the underlying mechanisms are not fully understood. Here, we report the gene regulation in HL-60 cells treated acutely with highly selective A3AR agonist MRS5698, positive allosteric modulator (PAM) LUF6000, or both. Both pro- and anti-inflammatory genes,...

This study describes the localization and computational prediction of a binding site for the A3 adenosine receptor (A3AR) positive allosteric modulator 2-cyclohexyl-1H-imidazo[4,5-c]quinolin-4-(3,4-dichlorophenyl)amine (LUF6000). The work reveals an extrahelical lipid-facing binding pocket disparate from the orthosteric binding site that encompasse...

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus...

Nucleoside diphosphates and triphosphates impact nearly every aspect of biochemistry; however, the use of such compounds as tools or medicinal leads for nucleotide-dependent enzymes and receptors is hampered by their rapid in vivo metabolism. Although a successful strategy to address the instability of the monophosphate moiety in oligonucleotide th...

Protein function strongly depends on temperature, which is related to temperature-dependent changes in the equilibria of protein conformational states. We leveraged variable-temperature ¹⁹ F-NMR spectroscopy to interrogate the temperature dependence of the conformational landscape of the human A 2A adenosine receptor (A 2A AR), a class A GPCR. Temp...

Receptor agonists and antagonists and other modulators of purinergic signalling have potential as novel therapeutics for a broad range of diseases and conditions. This special issue focuses on compounds or approaches that are either in clinical trials or headed in that direction. It is intended to serve as an up-to-date description of selected effo...

P2X7 receptor (P2X7R) has a key role in different pathological conditions, importantly overexpressed and activated in cancers. We explored the structure activity relationship (SAR) of three novel pyrazines, quinoline-carboxamide and oxadiazole series. Their selective inhibitory potency in Ca2+ mobilization assay using h-P2X7R-MCF-7 cells improved w...

Objectives: Cannabidiol (CBD) is a phytocannabinoid with great potential in clinical applications. The mechanism(s) of action of CBD require further investigation. Previous studies suggested that adenosine A2A receptors (A2ARs) could play a role in CBD-induced effects. Here, we evaluated the ability of CBD to modify the function of A2AR. Methods:...

Polo-like kinase 1 (Plk1) is considered an attractive target for anticancer therapy. Over the years, studies on the noncatalytic polo-box domain (PBD) of Plk1 have raised the expectation of generating highly specific protein-protein interaction inhibitors. However, the molecular nature of the canonical PBD-dependent interaction, which requires exte...

Based on hA2AAR structures, a hydrophobic C8-heteroaromatic ring in 5'-truncated adenosine analogues occupies the subpocket tightly, converting hA2AAR agonists into antagonists while maintaining affinity toward hA3AR. The final compounds of 2,8-disubstituted-N6-substituted 4'-thionucleosides, or 4'-oxo, were synthesized from d-mannose and d-erythro...

Three novel cytosine-derived α,β-methylene diphosphonates designated MRS4598, MRS4552, and MRS4602 were tested in the range of 1 × 10- 9 to 1 × 10- 3 M for their efficacy and potency in inhibiting membrane-bound ecto-5′-nucleotidase/CD73 activity in primary astrocytes in vitro. The compounds were also tested for their ability to attenuate the react...

Adenosine, P2Y, and P2X receptors have been the focus of purinergic ligand development in the pharmaceutical sector and academic medicinal chemistry laboratories for decades. However, so far, most of the clinical trials of selective adenosine and P2 receptor agonists and antagonists have not proven to be successful. Recent developments in the purin...

(N)-Methanocarba adenosine derivatives were structurally modified to target 5-HT2B serotonin receptors as antagonists, predominantly containing branched N6-alkyl groups. N6-Dicycloalkyl-methyl groups, including their asymmetric variations, as well as 2-iodo, were found to generally favor 5-HT2Rs, while only N6-dicyclohexyl-methyl derivative 35 show...

P2Y14 receptor (P2Y14R) is activated by extracellular UDP-glucose, a damage-associated molecular pattern that promotes inflammation in the kidney, lung, fat tissue, and elsewhere. Thus, selective P2Y14R antagonists are potentially useful for inflammatory and metabolic diseases. The piperidine ring size of potent, competitive P2Y14R antagonist (4-ph...

Numerous classes of selective agonists, antagonists, and allosteric modulators of the A3 adenosine receptor (AR) have been reported. The structure–affinity relationships and selectivity of A3AR ligands compared to the other three ARs have been described. Furthermore, prodrugs of some of these ligands have been reported, and their efficacy was demon...

Protein kinase C (PKC) isoforms regulate many important signaling pathways. Here, we report that PKC activation by phorbol 12-myristate 13-acetate (PMA) enhanced A2B adenosine receptor (AR)-mediated, but not β2-adrenergic receptor-mediated, cAMP accumulation, in H9C2 cardiomyocyte-like and HEK293 cells. In addition to enhancement, PKC (PMA-treatmen...

P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5, 189]) are activated by the endogenous ligands ATP, ADP, UTP, UDP, UDP-glucose and adenosine. The eight mammalian P2Y receptors are activated by distinct nucleotides: P2Y1, P2Y11, P2Y12 and P2Y13 are activated by adenosine-nucleotides; P2Y2, P2Y4 can be activ...

Adenosine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adenosine Receptors [112]) are activated by the endogenous ligand adenosine (potentially inosine also at A3 receptors). Crystal structures for the antagonist-bound [155, 316, 224, 62], agonist-bound [379, 205, 206] and G protein-bound A2A adenosine receptors [49] have been...

Terpenes are small hydrocarbon compounds that impart aroma and taste to many plants, including Cannabis sativa . A number of studies have shown that terpenes can produce pain relief in various pain states in both humans and animals. However, these studies were methodologically limited and few established mechanisms of action. In our previous work,...

Interest has been focused in recent years on the analgesic effects exerted by adenosine and its receptors, A1, A2A, A2B, and A3 adenosine receptor (AR) subtypes, in different in vivo models of chronic pain. In particular, it was demonstrated that selective A3AR agonists reduced pro-nociceptive N-type Ca2+ channels in dorsal root ganglion (DRG) neur...

The discovery and clinical implementation of modulators of adenosine, P2Y and P2X receptors have progressed dramatically in ∼50 years since Burnstock's definition of purinergic signaling. Although most clinical trials of selective ligands (agonists and antagonists) of these nineteen receptors failed, there is a renewed impetus to redirect efforts t...

Polo-like kinase 1 (Plk1), a mitotic kinase whose activity is widely upregulated in various human cancers, is considered an attractive target for anticancer drug discovery. Aside from the kinase domain, the C-terminal noncatalytic polo-box domain (PBD), which mediates the interaction with the enzyme's binding targets or substrates, has emerged as a...

Some non-adenosinergic drugs are reported to also act through adenosine receptors (ARs). We used mouse hypothermia, which can be induced by agonism at any of the four ARs, as an in vivo screen for adenosinergic effects. An AR contribution was identified when a drug caused hypothermia in wild type mice that was diminished in mice lacking all four AR...

G protein-coupled receptors (GPCRs) are embedded in phospholipids that strongly influence drug-stimulated signaling. Anionic lipids are particularly important for GPCR signaling complex formation, but a mechanism for this role is not understood. Using NMR spectroscopy, we explore the impact of anionic lipids on the function-related conformational e...

Background and Purpose: Identification of a novel treatment for ischemic stroke is urgently needed. We previously showed that genetic deletion as well as short term pharmacological inhibition of P2X4R, a purinergic receptor for adenosine triphosphate ATP, provides acute neuroprotection and thus can be potential drug targets to treat ischemic stroke...

CRC Press, Boca Raton, 2021. 452 pp., hardcover, €298.00.– ISBN 978‐1032063638

G protein-coupled receptors (GPCRs) are embedded in phospholipids that strongly influence drug-stimulated signaling. Anionic lipids are particularly important for GPCR signaling complex formation, but a mechanism for this role is not understood. Using NMR spectroscopy, we visualized the impact of anionic lipids on the function-related conformationa...

Efforts to fully understand pharmacological differences between G protein-coupled receptor (GPCR) species homologues are generally not pursued in detail during the drug development process. To date, many GPCRs that have been successfully targeted are relatively well-conserved across species in amino acid sequence and display minimal variability of...

Some non-adenosinergic drugs are reported to also act through adenosine receptors (ARs). We used mouse hypothermia, which can be induced by agonism at any of the four ARs, as an in vivo screen for adenosinergic effects. An AR contribution was identified when a drug caused hypothermia in wild type mice that was diminished in mice lacking all four AR...

Loss of bone is a common medical problem and, while it can be treated with available therapies, some of these therapies have critical side effects. We have previously demonstrated that CGS21680, a selective A 2A adenosine receptor agonist, prevents bone loss, but its on-target toxicities (hypotension, tachycardia) and frequent dosing requirements m...

Nucleoside diphosphates and triphosphates impact nearly every aspect of biochemistry, however, the use of such compounds as tools or medicinal leads for nucleotide-dependent enzymes and receptors is hampered due to rapid metabolism. Meanwhile, a successful strategy to address the instability of the monophosphate moiety in oligonucleotide therapeuti...

We previously reported 1H-imidazo[4,5-c]quinolin-4-amines as A3 adenosine receptor (A3AR) positive allosteric modulators (PAMs). A3AR agonists, but not PAMs, are in clinical trials for inflammatory diseases and liver conditions. We synthesized new analogues to distinguish 2-cyclopropyl antagonist 17 (orthosteric interaction demonstrated by binding...

Adenosine receptors (ARs) are involved in the suppression and development of inflammatory and fibrotic conditions. Specifically, AR activation promotes differentiation of lung fibroblasts into myofibroblasts, typical of a fibrotic event. Pulmonary fibrosis is a severe disease characterized by inflammation and fibrosis of unknown etiology and lackin...

COVID-19 disease is associated with progressive accumulation of SARS-CoV-2-specific mRNA, which is recognized by innate immune receptors, such as TLR3. This in turn leads to dysregulated production of multiple cytokines, including IL-6, IFN-γ, CXCL1, and TNF-α. Excessive production of these cytokines leads to acute lung injury (ALI), which conseque...

Resistance to pharmacotherapy requires the development of novel antiseizure drugs (ASDs). An adenosine A1 receptor (A1R) agonist, MRS5474, possesses anticonvulsant activity [1], without the cardiac side effects of other A1R agonists. We hypothesized that it could operate via a novel mechanism. We thus assessed its influence upon hippocampal excitat...

We analyzed the P2X4 receptor structure-activity relationship of a known antagonist 5, a 1,5-dihydro-2H-naphtho[1,2-b][1,4]diazepine-2,4(3H)-dione. Following extensive modification of the reported synthetic route, 4-pyridyl 21u (MRS4719) and 6-methyl 22c (MRS4596) analogues were most potent at human (h) P2X4R (IC50 0.503 and 1.38 μM, respectively,...

P2Y6 receptor (P2Y6R) antagonists represent potential drugs for treating cancer, pain, neurodegeneration, asthma, diabetes, colitis and other disorders. However, there are few chemical classes of known competitive antagonists. We recently explored the structure activity relationship (SAR) of 2H-chromene derivatives as P2Y6R antagonists of moderate...

Modulators of the G protein-coupled A2A adenosine receptor (A2AAR) have been considered promising agents to treat Parkinson's disease, inflammation, cancer, and central nervous system disorders. Herein, we demonstrate that a thiophene modification at the C8 position in the common adenine scaffold converted an A2AAR agonist into an antagonist. We sy...

The A3 adenosine receptor (A3AR) is a promising therapeutic target for inflammatory diseases, cancer, and chronic neuropathic pain, with agonists already in advanced clinical trials. Here we report an in-depth comparison of the pharmacological properties and structure-activity relationships of existing and expanded compound libraries of 2-substitut...

Resistance to pharmacotherapy requires the development of novel antiepileptic drugs (AEDs). An adenosine A1 receptor (A1R) agonist, MRS5474, possesses anticonvulsant activity (Tosh et al., 2012, J Med Chem, 55:8075), without the cardiac side effects of other A1R agonists. Hypothesizing that it operates via a novel mechanism, we assessed its influen...

Adenosine (ADO) is an extracellular signaling molecule generated locally under conditions that produce ischemia, hypoxia, or inflammation. It is involved in modulating a range of physiological functions throughout the brain and periphery through the membrane-bound G protein-coupled receptors, called adenosine receptors (ARs) A1AR, A2AAR, A2BAR, and...

Adenosine receptor (AR) ligands are being developed for metabolic, cardiovascular, neurological, and inflammatory diseases and cancer. The ease of drug discovery is contingent on the availability of pharmacological tools. Fluorescent antagonist ligands for the human A2A and A3ARs were synthesized using two validated pharmacophores, 1,3-dipropyl-8-p...

Epilepsy affects over 50 million people worldwide and increases the risk of death. An intrinsic state of central inflammation, mainly driven by TNFα/NFκB signaling, may contribute to the refractory nature of some epilepsies. We have therefore hypothesized that inhibitors of this signaling pathway might be therapeutic. To test this hypothesis, we ha...

Introduction: A3 adenosine receptor (A3 AR) agonists are currently being evaluated in clinical trials for treatment of inflammation, cancer, and neuropathic pain. To circumvent complications associated with the use of direct agonists of GPCRs (selectivity, dose-limiting side-effects), we have pursued development of A3 adenosine receptor positive a...

Chronic neuropathic pain is a major health issue and an economic burden that affects large numbers of people. Patients suffering from chronic pain have a significantly lowered quality of life, and to date there are no effective treatments for neuropathic pain. The P2Y14 receptor (P2Y14 R) is a purinergic G-protein coupled receptor that binds nucleo...

Adenosine in the tumor microenvironment acts on A2A and A2B adenosine receptors (ARs) on immune cells (T cells, dendritic cells, NK cells, macrophages and neutrophils) to prevent their activation. Therefore, a means of lowering extracellular adenosine would be beneficial in cancer immunotherapy either as a co-therapy or monotherapy. Inhibitors of C...

Background/Purpose: CD73 is a ecto-5′-nucleotidase located on the plasma membrane that generates adenosine from AMP in the extracellular space, and functions as a checkpoint against immune and vascular activation. CD73 inhibitors that eliminate this immune checkpoint blockade are being studied in phase 2/3 cancer clinical trials. We recently identi...

The A2A adenosine receptor is a protein belonging to a family of four GPCR adenosine receptors. It is involved in the regulation of several pathophysiological conditions in both the central nervous system and periphery. In the brain, its localization at pre- and postsynaptic level in striatum, cortex, hippocampus and its effects on glutamate releas...

Guanine nucleotides can flip between a North and South conformation in the ribose moiety. To test the enzymatic activity of GTPases bound to nucleotides in the two conformations, we generated methanocarba guanine nucleotides in the North or South envelope conformations, i.e., (N)-GTP and (S)-GTP, respectively. With dynamin as a model system, we exa...

Extracellular uridine nucleotides regulate physiological and pathophysiological metabolic processes through the activation of P2Y2, P2Y4, P2Y6 and P2Y14 purinergic receptors, which play a key role in adipogenesis, glucose uptake, lipolysis and adipokine secretion. Using adipocyte-specific knockout mouse models, it has been demonstrated that lack of...