The Experts below are selected from a list of 6609 Experts worldwide ranked by ideXlab platform
Kenneth A Jacobson - One of the best experts on this subject based on the ideXlab platform.
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historical and current Adenosine Receptor Agonists in preclinical and clinical development
Frontiers in Cellular Neuroscience, 2019Co-Authors: Kenneth A Jacobson, Dilip K Tosh, Shanu Jain, Zhanguo GaoAbstract:Adenosine Receptors (ARs) function in the body’s response to conditions of pathology and stress associated with a functional imbalance, such as in the supply and demand of energy/oxygen/nutrients. Extracellular Adenosine concentrations vary widely to raise or lower the basal activation of four subtypes of ARs. Endogenous Adenosine can correct an energy imbalance during hypoxia and other stress, for example, by slowing the heart rate by A1AR activation or increasing the blood supply to heart muscle by the A2AAR. Moreover, exogenous AR Agonists, antAgonists, or allosteric modulators can be applied for therapeutic benefit, and medicinal chemists working toward that goal have reported thousands of such agents. Thus, numerous clinical trials have ensued, using promising agents to modulate Adenosinergic signaling, most of which have not succeeded. Currently, short-acting, parenteral Agonists, Adenosine and Regadenoson, are the only AR Agonists approved for human use. However, new concepts and compounds are currently being developed and applied toward preclinical and clinical evaluation, and initial results are encouraging. This review focuses on key compounds as AR Agonists and positive allosteric modulators (PAMs) for disease treatment or diagnosis. AR Agonists for treating inflammation, pain, cancer, nonalcoholic steatohepatitis, angina, sickle cell disease, ischemic conditions and diabetes have been under development. Multiple clinical trials with two A3AR Agonists are ongoing
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A 1 Adenosine Receptor Agonists, AntAgonists, and Allosteric Modulators
The Adenosine Receptors, 2018Co-Authors: Zhanguo Gao, Dilip K Tosh, Shanu Jain, R. Rama Suresh, Kenneth A JacobsonAbstract:One of the four G protein-coupled Receptors for Adenosine, the A1 Adenosine Receptors (A1AR), is widely distributed in the body and modulates numerous normal and pathological processes, through signaling pathways including those downstream from its coupled Gi protein. It is an attractive drug target for heart failure, arrhythmias, angina, asthma, stroke, seizure, pain, depression, and diabetes. In this chapter, we describe the A1AR structure, function, signaling pathways, and therapeutic applications. We detail numerous structure-activity features of A1AR Agonists, antAgonists, and allosteric modulators, introduced as pharmacological tools and molecules for clinical development.
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scaffold repurposing of nucleosides Adenosine Receptor Agonists enhanced activity at the human dopamine and norepinephrine sodium symporters
Journal of Medicinal Chemistry, 2017Co-Authors: Dilip K Tosh, Eugene Warnick, Zhanguo Gao, John A. Auchampach, Aaron Janowsky, Amy J Eshleman, Zhoumou Chen, Elizabeth T Gizewski, Daniela Salvemini, Kenneth A JacobsonAbstract:We have repurposed (N)-methanocarba Adenosine derivatives (A3 Adenosine Receptor (AR) Agonists) to enhance radioligand binding allosterically at the human dopamine (DA) transporter (DAT) and inhibit DA uptake. We extended the structure–activity relationship of this series with small N6-alkyl substitution, 5′-esters, deaza modifications of adenine, and ribose restored in place of methanocarba. C2-(5-Halothien-2-yl)-ethynyl 5′-methyl 9 (MRS7292) and 5′-ethyl 10 (MRS7232) esters enhanced binding at DAT (EC50 ∼ 35 nM) and at the norepinephrine transporter (NET). 9 and 10 were selective for DAT compared to A3AR in the mouse but not in humans. At DAT, the binding of two structurally dissimilar radioligands was enhanced; NET binding of only one radioligand was enhanced; SERT radioligand binding was minimally affected. 10 was more potent than cocaine at inhibiting DA uptake (IC50 = 107 nM). Ribose analogues were weaker in DAT interaction than the corresponding bicyclics. Thus, we enhanced the neurotransmitter tra...
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spinal neuroimmune activation is independent of t cell infiltration and attenuated by a3 Adenosine Receptor Agonists in a model of oxaliplatin induced peripheral neuropathy
Brain Behavior and Immunity, 2015Co-Authors: Kali Janes, Kenneth A Jacobson, Dilip K Tosh, Carrie Wahlman, Joshua W Little, Timothy M Doyle, Daniela SalveminiAbstract:Many commonly used chemotherapeutics including oxaliplatin are associated with the development of a painful chemotherapy-induced peripheral neuropathy (CIPN). This dose-limiting complication can appear long after the completion of therapy causing a significant reduction in quality-of-life and impeding cancer treatment. We recently reported that activation of the Gi/Gq-coupled A3 Adenosine Receptor (A3AR) with selective A3AR Agonists (i.e., IB-MECA) blocked the development of chemotherapy induced-neuropathic pain in models evoked by distinct agents including oxaliplatin without interfering with their anticancer activities. The mechanism(s) of action underlying these beneficial effects has yet to be explored. Our results herein demonstrate that the development of oxaliplatin-induced mechano-hypersensitivity (allodynia and hyperalgesia) in rats is associated with the hyperactivation of astrocytes, but not microglial cells, increased production of pro-inflammatory and neuroexcitatory cytokines (TNF, IL-1β), and reductions in the levels of anti-inflammatory/neuroprotective cytokines (IL-10, IL-4) in the dorsal horn of the spinal cord. These events did not require lymphocytic mobilization since oxaliplatin did not induce CD45(+)/CD3(+) T-cell infiltration into the spinal cord. A3AR Agonists blocked the development of neuropathic pain with beneficial effects strongly associated with the modulation of spinal neuroinflammatory processes: attenuation of astrocytic hyperactivation, inhibition of TNF and IL-1β production, and an increase in IL-10 and IL-4. These results suggest that inhibition of an astrocyte-associated neuroinflammatory response contributes to the protective actions of A3AR signaling and continues to support the pharmacological basis for selective A3AR Agonists as adjuncts to chemotherapeutic agents for the management of chronic pain.
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In Vivo Phenotypic Screening for Treating Chronic Neuropathic Pain: Modification of C2‑Arylethynyl Group of Conformationally Constrained A3 Adenosine Receptor Agonists
2015Co-Authors: Dilip K Tosh, Zhanguo Gao, John A. Auchampach, Elizabeth T Gizewski, Daniela Salvemini, Amanda Finley, Silvia Paoletta, Steven M. Moss, Kenneth A JacobsonAbstract:(N)-Methanocarba Adenosine 5′-methyluronamides containing 2-arylethynyl groups were synthesized as A3 Adenosine Receptor (AR) Agonists and screened in vivo (po) for reduction of neuropathic pain. A small N6-methyl group maintained binding affinity, with human > mouse A3AR and MW < 500 and other favorable physicochemical properties. Emax (maximal efficacy in a mouse chronic constriction injury pain model) of previously characterized A3AR agonist, 2-(3,4-difluorophenylethynyl)-N6-(3-chlorobenzyl) derivative 6a, MRS5698, was surpassed. More efficacious analogues (in vivo) contained the following C2-arylethynyl groups: pyrazin-2-yl 23 (binding Ki, hA3AR, nM 1.8), fur-2-yl 27 (0.6), thien-2-yl 32 (0.6) and its 5-chloro 33, MRS5980 (0.7) and 5-bromo 34 (0.4) equivalents, and physiologically unstable ferrocene 36, MRS5979 (2.7). 33 and 36 displayed particularly long in vivo duration (>3 h). Selected analogues were docked to an A3AR homology model to explore the environment of Receptor-bound C2 and N6 groups. Various analogues bound with μM affinity at off-target biogenic amine (M2, 5HT2A, β3, 5HT2B, 5HT2C, and α2C) or other Receptors. Thus, we have expanded the structural range of orally active A3AR Agonists for chronic pain treatment
Zhanguo Gao - One of the best experts on this subject based on the ideXlab platform.
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historical and current Adenosine Receptor Agonists in preclinical and clinical development
Frontiers in Cellular Neuroscience, 2019Co-Authors: Kenneth A Jacobson, Dilip K Tosh, Shanu Jain, Zhanguo GaoAbstract:Adenosine Receptors (ARs) function in the body’s response to conditions of pathology and stress associated with a functional imbalance, such as in the supply and demand of energy/oxygen/nutrients. Extracellular Adenosine concentrations vary widely to raise or lower the basal activation of four subtypes of ARs. Endogenous Adenosine can correct an energy imbalance during hypoxia and other stress, for example, by slowing the heart rate by A1AR activation or increasing the blood supply to heart muscle by the A2AAR. Moreover, exogenous AR Agonists, antAgonists, or allosteric modulators can be applied for therapeutic benefit, and medicinal chemists working toward that goal have reported thousands of such agents. Thus, numerous clinical trials have ensued, using promising agents to modulate Adenosinergic signaling, most of which have not succeeded. Currently, short-acting, parenteral Agonists, Adenosine and Regadenoson, are the only AR Agonists approved for human use. However, new concepts and compounds are currently being developed and applied toward preclinical and clinical evaluation, and initial results are encouraging. This review focuses on key compounds as AR Agonists and positive allosteric modulators (PAMs) for disease treatment or diagnosis. AR Agonists for treating inflammation, pain, cancer, nonalcoholic steatohepatitis, angina, sickle cell disease, ischemic conditions and diabetes have been under development. Multiple clinical trials with two A3AR Agonists are ongoing
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A 1 Adenosine Receptor Agonists, AntAgonists, and Allosteric Modulators
The Adenosine Receptors, 2018Co-Authors: Zhanguo Gao, Dilip K Tosh, Shanu Jain, R. Rama Suresh, Kenneth A JacobsonAbstract:One of the four G protein-coupled Receptors for Adenosine, the A1 Adenosine Receptors (A1AR), is widely distributed in the body and modulates numerous normal and pathological processes, through signaling pathways including those downstream from its coupled Gi protein. It is an attractive drug target for heart failure, arrhythmias, angina, asthma, stroke, seizure, pain, depression, and diabetes. In this chapter, we describe the A1AR structure, function, signaling pathways, and therapeutic applications. We detail numerous structure-activity features of A1AR Agonists, antAgonists, and allosteric modulators, introduced as pharmacological tools and molecules for clinical development.
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n6 substituted 5 n methylcarbamoyl 4 selenoAdenosines as potent and selective a3 Adenosine Receptor Agonists with unusual sugar puckering and nucleobase orientation
Journal of Medicinal Chemistry, 2017Co-Authors: Long Xuan Zhao, Jongmi Park, Hyuk Woo Lee, Pramod K Sahu, Minghua Cui, Steven M Moss, Eva Hammes, Eugene Warnick, Zhanguo Gao, Minsoo NohAbstract:Potent and selective A3 Adenosine Receptor (AR) Agonists were identified by the replacement of 4′-oxo- or 4′-thionucleosides with bioisosteric selenium. Unlike previous Agonists, 4′-seleno analogues preferred a glycosidic syn conformation and South sugar puckering, as shown in the X-ray crystal structure of 5′-N-methylcarbamoyl derivative 3p. Among the compounds tested, N6-3-iodobenzyl analogue 3d was found to be the most potent A3AR full agonist (Ki = 0.57 nM), which was ≥800- and 1900-fold selective for A1AR and A2AAR, respectively. In the N6-cycloalkyl series, 2-Cl analogues generally exhibited better hA3AR affinity than 2-H analogues, whereas 2-H > 2-Cl in the N6-3-halobenzyl series. N7 isomers 3t and 3u were much weaker in binding than corresponding N9 isomers, but compound 3t lacked A3AR activation, appearing to be a weak antagonist. 2-Cl-N6-3-iodobenzyl analogue 3p inhibited chemoattractant-induced migration of microglia/monocytes without inducing cell death at ≤50 μM. This suggests the potential f...
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scaffold repurposing of nucleosides Adenosine Receptor Agonists enhanced activity at the human dopamine and norepinephrine sodium symporters
Journal of Medicinal Chemistry, 2017Co-Authors: Dilip K Tosh, Eugene Warnick, Zhanguo Gao, John A. Auchampach, Aaron Janowsky, Amy J Eshleman, Zhoumou Chen, Elizabeth T Gizewski, Daniela Salvemini, Kenneth A JacobsonAbstract:We have repurposed (N)-methanocarba Adenosine derivatives (A3 Adenosine Receptor (AR) Agonists) to enhance radioligand binding allosterically at the human dopamine (DA) transporter (DAT) and inhibit DA uptake. We extended the structure–activity relationship of this series with small N6-alkyl substitution, 5′-esters, deaza modifications of adenine, and ribose restored in place of methanocarba. C2-(5-Halothien-2-yl)-ethynyl 5′-methyl 9 (MRS7292) and 5′-ethyl 10 (MRS7232) esters enhanced binding at DAT (EC50 ∼ 35 nM) and at the norepinephrine transporter (NET). 9 and 10 were selective for DAT compared to A3AR in the mouse but not in humans. At DAT, the binding of two structurally dissimilar radioligands was enhanced; NET binding of only one radioligand was enhanced; SERT radioligand binding was minimally affected. 10 was more potent than cocaine at inhibiting DA uptake (IC50 = 107 nM). Ribose analogues were weaker in DAT interaction than the corresponding bicyclics. Thus, we enhanced the neurotransmitter tra...
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N6‑Substituted 5′‑N‑Methylcarbamoyl-4′-selenoAdenosines as Potent and Selective A3 Adenosine Receptor Agonists with Unusual Sugar Puckering and Nucleobase Orientation
2017Co-Authors: Long Xuan Zhao, Jongmi Park, Hyuk Woo Lee, Pramod K Sahu, Minghua Cui, Steven M Moss, Eva Hammes, Eugene Warnick, Zhanguo GaoAbstract:Potent and selective A3 Adenosine Receptor (AR) Agonists were identified by the replacement of 4′-oxo- or 4′-thionucleosides with bioisosteric selenium. Unlike previous Agonists, 4′-seleno analogues preferred a glycosidic syn conformation and South sugar puckering, as shown in the X-ray crystal structure of 5′-N-methylcarbamoyl derivative 3p. Among the compounds tested, N6-3-iodobenzyl analogue 3d was found to be the most potent A3AR full agonist (Ki = 0.57 nM), which was ≥800- and 1900-fold selective for A1AR and A2AAR, respectively. In the N6-cycloalkyl series, 2-Cl analogues generally exhibited better hA3AR affinity than 2-H analogues, whereas 2-H > 2-Cl in the N6-3-halobenzyl series. N7 isomers 3t and 3u were much weaker in binding than corresponding N9 isomers, but compound 3t lacked A3AR activation, appearing to be a weak antagonist. 2-Cl-N6-3-iodobenzyl analogue 3p inhibited chemoattractant-induced migration of microglia/monocytes without inducing cell death at ≤50 μM. This suggests the potential for the development of 4′-selenonucleoside A3AR Agonists as novel antistroke agents
Dilip K Tosh - One of the best experts on this subject based on the ideXlab platform.
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historical and current Adenosine Receptor Agonists in preclinical and clinical development
Frontiers in Cellular Neuroscience, 2019Co-Authors: Kenneth A Jacobson, Dilip K Tosh, Shanu Jain, Zhanguo GaoAbstract:Adenosine Receptors (ARs) function in the body’s response to conditions of pathology and stress associated with a functional imbalance, such as in the supply and demand of energy/oxygen/nutrients. Extracellular Adenosine concentrations vary widely to raise or lower the basal activation of four subtypes of ARs. Endogenous Adenosine can correct an energy imbalance during hypoxia and other stress, for example, by slowing the heart rate by A1AR activation or increasing the blood supply to heart muscle by the A2AAR. Moreover, exogenous AR Agonists, antAgonists, or allosteric modulators can be applied for therapeutic benefit, and medicinal chemists working toward that goal have reported thousands of such agents. Thus, numerous clinical trials have ensued, using promising agents to modulate Adenosinergic signaling, most of which have not succeeded. Currently, short-acting, parenteral Agonists, Adenosine and Regadenoson, are the only AR Agonists approved for human use. However, new concepts and compounds are currently being developed and applied toward preclinical and clinical evaluation, and initial results are encouraging. This review focuses on key compounds as AR Agonists and positive allosteric modulators (PAMs) for disease treatment or diagnosis. AR Agonists for treating inflammation, pain, cancer, nonalcoholic steatohepatitis, angina, sickle cell disease, ischemic conditions and diabetes have been under development. Multiple clinical trials with two A3AR Agonists are ongoing
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design and in vivo characterization of a1 Adenosine Receptor Agonists in the native ribose and conformationally constrained n methanocarba series
Journal of Medicinal Chemistry, 2019Co-Authors: Dilip K Tosh, Harsha Rao, Amelia Bitant, Veronica Salmaso, Philip Mannes, David I. Lieberman, Kelli L. Vaughan, Julie A. Mattison, Amy C. RothwellAbstract:(N)-Methanocarba ([3.1.0]bicyclohexyl) Adenosines and corresponding ribosides were synthesized to identify novel A1 Adenosine Receptor (A1AR) Agonists for CNS or peripheral applications. Human and mouse AR binding was determined to assess the constrained ring system’s A1AR compatibility. N6-Dicyclobutylmethyl ribose agonist (9, MRS7469, >2000-fold selective for A1AR) and known truncated N6-dicyclopropylmethyl methanocarba 7 (MRS5474) were drug-like. The pure diastereoisomer of known riboside 4 displayed high hA1AR selectivity. Methanocarba modification reduced A1AR selectivity of N6-dicyclopropylmethyl and endo-norbornylAdenosines but increased ribavirin selectivity. Most analogues tested (ip) were inactive or weak in inducing mouse hypothermia, despite mA1AR full agonism and variable mA3AR efficacy, but strong hypothermia by 9 depended on A1AR, which reflects CNS activity (determined using A1AR or A3AR null mice). Conserved hA1AR interactions were preserved in modeling of 9 and methanocarba equivalent 24...
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repurposing of a nucleoside scaffold from Adenosine Receptor Agonists to opioid Receptor antAgonists
ACS Omega, 2018Co-Authors: Dilip K Tosh, Eugene Warnick, Philip Mannes, Aaron Janowsky, Amy J Eshleman, Elizabeth T Gizewski, Antonella Ciancetta, Tarsis F Brust, Laura M Bohn, John A. AuchampachAbstract:While screening off-target effects of rigid (N)-methanocarba-Adenosine 5′-methylamides as A3 Adenosine Receptor (AR) Agonists, we discovered μM binding hits at the δ-opioid Receptor (DOR) and translocator protein (TSPO). In an effort to increase OR and decrease AR affinity by structure activity analysis of this series, antagonist activity at κ-(K)OR appeared in 5′-esters (ethyl 24 and propyl 30), which retained TSPO interaction (μM). 7-Deaza modification of C2-(arylethynyl)-5′-esters but not 4′-truncation enhanced KOR affinity (MRS7299 28 and 29, Ki ≈ 40 nM), revealed μ-OR and DOR binding, and reduced AR affinity. Molecular docking and dynamics simulations located a putative KOR binding mode consistent with the observed affinities, placing C7 in a hydrophobic region. 3-Deaza modification permitted TSPO but not OR binding, and 1-deaza was permissive to both; ribose-restored analogues were inactive at both. Thus, we have repurposed a known AR nucleoside scaffold for OR antagonism, with a detailed hypothesis...
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A 1 Adenosine Receptor Agonists, AntAgonists, and Allosteric Modulators
The Adenosine Receptors, 2018Co-Authors: Zhanguo Gao, Dilip K Tosh, Shanu Jain, R. Rama Suresh, Kenneth A JacobsonAbstract:One of the four G protein-coupled Receptors for Adenosine, the A1 Adenosine Receptors (A1AR), is widely distributed in the body and modulates numerous normal and pathological processes, through signaling pathways including those downstream from its coupled Gi protein. It is an attractive drug target for heart failure, arrhythmias, angina, asthma, stroke, seizure, pain, depression, and diabetes. In this chapter, we describe the A1AR structure, function, signaling pathways, and therapeutic applications. We detail numerous structure-activity features of A1AR Agonists, antAgonists, and allosteric modulators, introduced as pharmacological tools and molecules for clinical development.
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scaffold repurposing of nucleosides Adenosine Receptor Agonists enhanced activity at the human dopamine and norepinephrine sodium symporters
Journal of Medicinal Chemistry, 2017Co-Authors: Dilip K Tosh, Eugene Warnick, Zhanguo Gao, John A. Auchampach, Aaron Janowsky, Amy J Eshleman, Zhoumou Chen, Elizabeth T Gizewski, Daniela Salvemini, Kenneth A JacobsonAbstract:We have repurposed (N)-methanocarba Adenosine derivatives (A3 Adenosine Receptor (AR) Agonists) to enhance radioligand binding allosterically at the human dopamine (DA) transporter (DAT) and inhibit DA uptake. We extended the structure–activity relationship of this series with small N6-alkyl substitution, 5′-esters, deaza modifications of adenine, and ribose restored in place of methanocarba. C2-(5-Halothien-2-yl)-ethynyl 5′-methyl 9 (MRS7292) and 5′-ethyl 10 (MRS7232) esters enhanced binding at DAT (EC50 ∼ 35 nM) and at the norepinephrine transporter (NET). 9 and 10 were selective for DAT compared to A3AR in the mouse but not in humans. At DAT, the binding of two structurally dissimilar radioligands was enhanced; NET binding of only one radioligand was enhanced; SERT radioligand binding was minimally affected. 10 was more potent than cocaine at inhibiting DA uptake (IC50 = 107 nM). Ribose analogues were weaker in DAT interaction than the corresponding bicyclics. Thus, we enhanced the neurotransmitter tra...
Daniela Salvemini - One of the best experts on this subject based on the ideXlab platform.
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scaffold repurposing of nucleosides Adenosine Receptor Agonists enhanced activity at the human dopamine and norepinephrine sodium symporters
Journal of Medicinal Chemistry, 2017Co-Authors: Dilip K Tosh, Eugene Warnick, Zhanguo Gao, John A. Auchampach, Aaron Janowsky, Amy J Eshleman, Zhoumou Chen, Elizabeth T Gizewski, Daniela Salvemini, Kenneth A JacobsonAbstract:We have repurposed (N)-methanocarba Adenosine derivatives (A3 Adenosine Receptor (AR) Agonists) to enhance radioligand binding allosterically at the human dopamine (DA) transporter (DAT) and inhibit DA uptake. We extended the structure–activity relationship of this series with small N6-alkyl substitution, 5′-esters, deaza modifications of adenine, and ribose restored in place of methanocarba. C2-(5-Halothien-2-yl)-ethynyl 5′-methyl 9 (MRS7292) and 5′-ethyl 10 (MRS7232) esters enhanced binding at DAT (EC50 ∼ 35 nM) and at the norepinephrine transporter (NET). 9 and 10 were selective for DAT compared to A3AR in the mouse but not in humans. At DAT, the binding of two structurally dissimilar radioligands was enhanced; NET binding of only one radioligand was enhanced; SERT radioligand binding was minimally affected. 10 was more potent than cocaine at inhibiting DA uptake (IC50 = 107 nM). Ribose analogues were weaker in DAT interaction than the corresponding bicyclics. Thus, we enhanced the neurotransmitter tra...
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purine n methanocarba nucleoside derivatives lacking an exocyclic amine as selective a3 Adenosine Receptor Agonists
Journal of Medicinal Chemistry, 2016Co-Authors: Dilip K Tosh, Eugene Warnick, Zhanguo Gao, John A. Auchampach, Zhoumou Chen, Elizabeth T Gizewski, Antonella Ciancetta, Robert D Oconnor, Steven Crane, Daniela SalveminiAbstract:Purine (N)-methanocarba-5′-N-alkyluronamidoriboside A3 Adenosine Receptor (A3AR) Agonists lacking an exocyclic amine resulted from an unexpected reaction during a Sonogashira coupling and subsequent aminolysis. Because the initial C6-Me and C6-styryl derivatives had unexpectedly high A3AR affinity, other rigid nucleoside analogues lacking an exocyclic amine were prepared. Of these, the C6-Me-(2-phenylethynyl) and C2-(5-chlorothienylethynyl) analogues were particularly potent, with human A3AR Ki values of 6 and 42 nM, respectively. Additionally, the C2-(5-chlorothienyl)-6-H analogue was potent and selective at A3AR (MRS7220, Ki 60 nM) and also completely reversed mouse sciatic nerve mechanoallodynia (in vivo, 3 μmol/kg, po). The lack of a C6 H-bond donor while maintaining A3AR affinity and efficacy could be rationalized by homology modeling and docking of these hypermodified nucleosides. The modeling suggests that a suitable combination of stabilizing features can partially compensate for the lack of an ex...
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Purine (N)‑Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A3 Adenosine Receptor Agonists
2016Co-Authors: Dilip K. Tosh, Eugene Warnick, Zhanguo Gao, John A. Auchampach, Zhoumou Chen, Elizabeth T Gizewski, Antonella Ciancetta, Steven Crane, Robert O’connor, Daniela SalveminiAbstract:Purine (N)-methanocarba-5′-N-alkyluronamidoriboside A3 Adenosine Receptor (A3AR) Agonists lacking an exocyclic amine resulted from an unexpected reaction during a Sonogashira coupling and subsequent aminolysis. Because the initial C6-Me and C6-styryl derivatives had unexpectedly high A3AR affinity, other rigid nucleoside analogues lacking an exocyclic amine were prepared. Of these, the C6-Me-(2-phenylethynyl) and C2-(5-chlorothienylethynyl) analogues were particularly potent, with human A3AR Ki values of 6 and 42 nM, respectively. Additionally, the C2-(5-chlorothienyl)-6-H analogue was potent and selective at A3AR (MRS7220, Ki 60 nM) and also completely reversed mouse sciatic nerve mechanoallodynia (in vivo, 3 μmol/kg, po). The lack of a C6 H-bond donor while maintaining A3AR affinity and efficacy could be rationalized by homology modeling and docking of these hypermodified nucleosides. The modeling suggests that a suitable combination of stabilizing features can partially compensate for the lack of an exocyclic amine, an otherwise important contributor to recognition in the A3AR binding site
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spinal neuroimmune activation is independent of t cell infiltration and attenuated by a3 Adenosine Receptor Agonists in a model of oxaliplatin induced peripheral neuropathy
Brain Behavior and Immunity, 2015Co-Authors: Kali Janes, Kenneth A Jacobson, Dilip K Tosh, Carrie Wahlman, Joshua W Little, Timothy M Doyle, Daniela SalveminiAbstract:Many commonly used chemotherapeutics including oxaliplatin are associated with the development of a painful chemotherapy-induced peripheral neuropathy (CIPN). This dose-limiting complication can appear long after the completion of therapy causing a significant reduction in quality-of-life and impeding cancer treatment. We recently reported that activation of the Gi/Gq-coupled A3 Adenosine Receptor (A3AR) with selective A3AR Agonists (i.e., IB-MECA) blocked the development of chemotherapy induced-neuropathic pain in models evoked by distinct agents including oxaliplatin without interfering with their anticancer activities. The mechanism(s) of action underlying these beneficial effects has yet to be explored. Our results herein demonstrate that the development of oxaliplatin-induced mechano-hypersensitivity (allodynia and hyperalgesia) in rats is associated with the hyperactivation of astrocytes, but not microglial cells, increased production of pro-inflammatory and neuroexcitatory cytokines (TNF, IL-1β), and reductions in the levels of anti-inflammatory/neuroprotective cytokines (IL-10, IL-4) in the dorsal horn of the spinal cord. These events did not require lymphocytic mobilization since oxaliplatin did not induce CD45(+)/CD3(+) T-cell infiltration into the spinal cord. A3AR Agonists blocked the development of neuropathic pain with beneficial effects strongly associated with the modulation of spinal neuroinflammatory processes: attenuation of astrocytic hyperactivation, inhibition of TNF and IL-1β production, and an increase in IL-10 and IL-4. These results suggest that inhibition of an astrocyte-associated neuroinflammatory response contributes to the protective actions of A3AR signaling and continues to support the pharmacological basis for selective A3AR Agonists as adjuncts to chemotherapeutic agents for the management of chronic pain.
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In Vivo Phenotypic Screening for Treating Chronic Neuropathic Pain: Modification of C2‑Arylethynyl Group of Conformationally Constrained A3 Adenosine Receptor Agonists
2015Co-Authors: Dilip K Tosh, Zhanguo Gao, John A. Auchampach, Elizabeth T Gizewski, Daniela Salvemini, Amanda Finley, Silvia Paoletta, Steven M. Moss, Kenneth A JacobsonAbstract:(N)-Methanocarba Adenosine 5′-methyluronamides containing 2-arylethynyl groups were synthesized as A3 Adenosine Receptor (AR) Agonists and screened in vivo (po) for reduction of neuropathic pain. A small N6-methyl group maintained binding affinity, with human > mouse A3AR and MW < 500 and other favorable physicochemical properties. Emax (maximal efficacy in a mouse chronic constriction injury pain model) of previously characterized A3AR agonist, 2-(3,4-difluorophenylethynyl)-N6-(3-chlorobenzyl) derivative 6a, MRS5698, was surpassed. More efficacious analogues (in vivo) contained the following C2-arylethynyl groups: pyrazin-2-yl 23 (binding Ki, hA3AR, nM 1.8), fur-2-yl 27 (0.6), thien-2-yl 32 (0.6) and its 5-chloro 33, MRS5980 (0.7) and 5-bromo 34 (0.4) equivalents, and physiologically unstable ferrocene 36, MRS5979 (2.7). 33 and 36 displayed particularly long in vivo duration (>3 h). Selected analogues were docked to an A3AR homology model to explore the environment of Receptor-bound C2 and N6 groups. Various analogues bound with μM affinity at off-target biogenic amine (M2, 5HT2A, β3, 5HT2B, 5HT2C, and α2C) or other Receptors. Thus, we have expanded the structural range of orally active A3AR Agonists for chronic pain treatment
John A. Auchampach - One of the best experts on this subject based on the ideXlab platform.
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Design and in Vivo Characterization of A1 Adenosine Receptor Agonists in the Native Ribose and Conformationally Constrained (N)-Methanocarba Series
2019Co-Authors: Dilip K. Tosh, Harsha Rao, Amelia Bitant, Veronica Salmaso, Philip Mannes, David I. Lieberman, Kelli L. Vaughan, Julie A. Mattison, Amy C. Rothwell, John A. AuchampachAbstract:(N)-Methanocarba ([3.1.0]bicyclohexyl) Adenosines and corresponding ribosides were synthesized to identify novel A1 Adenosine Receptor (A1AR) Agonists for CNS or peripheral applications. Human and mouse AR binding was determined to assess the constrained ring system’s A1AR compatibility. N6-Dicyclobutylmethyl ribose agonist (9, MRS7469, >2000-fold selective for A1AR) and known truncated N6-dicyclopropylmethyl methanocarba 7 (MRS5474) were drug-like. The pure diastereoisomer of known riboside 4 displayed high hA1AR selectivity. Methanocarba modification reduced A1AR selectivity of N6-dicyclopropylmethyl and endo-norbornylAdenosines but increased ribavirin selectivity. Most analogues tested (ip) were inactive or weak in inducing mouse hypothermia, despite mA1AR full agonism and variable mA3AR efficacy, but strong hypothermia by 9 depended on A1AR, which reflects CNS activity (determined using A1AR or A3AR null mice). Conserved hA1AR interactions were preserved in modeling of 9 and methanocarba equivalent 24 (∼400-fold A1AR-selective). Thus, we identified, and characterized in vivo, ribose and methanocarba nucleosides, including with A1AR-enhancing N6-dicyclobutylmethyl-adenine and 1,2,4-triazole-3-carboxamide (40, MRS7451) nucleobases
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repurposing of a nucleoside scaffold from Adenosine Receptor Agonists to opioid Receptor antAgonists
ACS Omega, 2018Co-Authors: Dilip K Tosh, Eugene Warnick, Philip Mannes, Aaron Janowsky, Amy J Eshleman, Elizabeth T Gizewski, Antonella Ciancetta, Tarsis F Brust, Laura M Bohn, John A. AuchampachAbstract:While screening off-target effects of rigid (N)-methanocarba-Adenosine 5′-methylamides as A3 Adenosine Receptor (AR) Agonists, we discovered μM binding hits at the δ-opioid Receptor (DOR) and translocator protein (TSPO). In an effort to increase OR and decrease AR affinity by structure activity analysis of this series, antagonist activity at κ-(K)OR appeared in 5′-esters (ethyl 24 and propyl 30), which retained TSPO interaction (μM). 7-Deaza modification of C2-(arylethynyl)-5′-esters but not 4′-truncation enhanced KOR affinity (MRS7299 28 and 29, Ki ≈ 40 nM), revealed μ-OR and DOR binding, and reduced AR affinity. Molecular docking and dynamics simulations located a putative KOR binding mode consistent with the observed affinities, placing C7 in a hydrophobic region. 3-Deaza modification permitted TSPO but not OR binding, and 1-deaza was permissive to both; ribose-restored analogues were inactive at both. Thus, we have repurposed a known AR nucleoside scaffold for OR antagonism, with a detailed hypothesis...
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Repurposing of a Nucleoside Scaffold from Adenosine Receptor Agonists to Opioid Receptor AntAgonists
2018Co-Authors: Dilip K. Tosh, Eugene Warnick, Philip Mannes, Aaron Janowsky, Amy J Eshleman, Elizabeth T Gizewski, Antonella Ciancetta, Tarsis F Brust, Laura M Bohn, John A. AuchampachAbstract:While screening off-target effects of rigid (N)-methanocarba-Adenosine 5′-methylamides as A3 Adenosine Receptor (AR) Agonists, we discovered μM binding hits at the δ-opioid Receptor (DOR) and translocator protein (TSPO). In an effort to increase OR and decrease AR affinity by structure activity analysis of this series, antagonist activity at κ-(K)OR appeared in 5′-esters (ethyl 24 and propyl 30), which retained TSPO interaction (μM). 7-Deaza modification of C2-(arylethynyl)-5′-esters but not 4′-truncation enhanced KOR affinity (MRS7299 28 and 29, Ki ≈ 40 nM), revealed μ-OR and DOR binding, and reduced AR affinity. Molecular docking and dynamics simulations located a putative KOR binding mode consistent with the observed affinities, placing C7 in a hydrophobic region. 3-Deaza modification permitted TSPO but not OR binding, and 1-deaza was permissive to both; ribose-restored analogues were inactive at both. Thus, we have repurposed a known AR nucleoside scaffold for OR antagonism, with a detailed hypothesis for KOR recognition
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scaffold repurposing of nucleosides Adenosine Receptor Agonists enhanced activity at the human dopamine and norepinephrine sodium symporters
Journal of Medicinal Chemistry, 2017Co-Authors: Dilip K Tosh, Eugene Warnick, Zhanguo Gao, John A. Auchampach, Aaron Janowsky, Amy J Eshleman, Zhoumou Chen, Elizabeth T Gizewski, Daniela Salvemini, Kenneth A JacobsonAbstract:We have repurposed (N)-methanocarba Adenosine derivatives (A3 Adenosine Receptor (AR) Agonists) to enhance radioligand binding allosterically at the human dopamine (DA) transporter (DAT) and inhibit DA uptake. We extended the structure–activity relationship of this series with small N6-alkyl substitution, 5′-esters, deaza modifications of adenine, and ribose restored in place of methanocarba. C2-(5-Halothien-2-yl)-ethynyl 5′-methyl 9 (MRS7292) and 5′-ethyl 10 (MRS7232) esters enhanced binding at DAT (EC50 ∼ 35 nM) and at the norepinephrine transporter (NET). 9 and 10 were selective for DAT compared to A3AR in the mouse but not in humans. At DAT, the binding of two structurally dissimilar radioligands was enhanced; NET binding of only one radioligand was enhanced; SERT radioligand binding was minimally affected. 10 was more potent than cocaine at inhibiting DA uptake (IC50 = 107 nM). Ribose analogues were weaker in DAT interaction than the corresponding bicyclics. Thus, we enhanced the neurotransmitter tra...
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purine n methanocarba nucleoside derivatives lacking an exocyclic amine as selective a3 Adenosine Receptor Agonists
Journal of Medicinal Chemistry, 2016Co-Authors: Dilip K Tosh, Eugene Warnick, Zhanguo Gao, John A. Auchampach, Zhoumou Chen, Elizabeth T Gizewski, Antonella Ciancetta, Robert D Oconnor, Steven Crane, Daniela SalveminiAbstract:Purine (N)-methanocarba-5′-N-alkyluronamidoriboside A3 Adenosine Receptor (A3AR) Agonists lacking an exocyclic amine resulted from an unexpected reaction during a Sonogashira coupling and subsequent aminolysis. Because the initial C6-Me and C6-styryl derivatives had unexpectedly high A3AR affinity, other rigid nucleoside analogues lacking an exocyclic amine were prepared. Of these, the C6-Me-(2-phenylethynyl) and C2-(5-chlorothienylethynyl) analogues were particularly potent, with human A3AR Ki values of 6 and 42 nM, respectively. Additionally, the C2-(5-chlorothienyl)-6-H analogue was potent and selective at A3AR (MRS7220, Ki 60 nM) and also completely reversed mouse sciatic nerve mechanoallodynia (in vivo, 3 μmol/kg, po). The lack of a C6 H-bond donor while maintaining A3AR affinity and efficacy could be rationalized by homology modeling and docking of these hypermodified nucleosides. The modeling suggests that a suitable combination of stabilizing features can partially compensate for the lack of an ex...