A1 Adenosine Receptor Agonists, Antagonists, and Allosteric Modulators

Gao, Zhan‐Guo; Tosh, Dilip K.; Jain, Shanu; Yu, Jinha; Suresh, R. Rama; Jacobson, Kenneth A.

doi:10.1007/978-3-319-90808-3_4

Cited by 19 publications

(22 citation statements)

References 197 publications

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“…[92]). An antinociceptive and neuroprotective traditional Chinese medicine containing paeoniflorin, a monoterpene glucoside isolated from peony root, has allosteric A 1 AR activation as its putative mechanism of action, but pharmacologically distinct from 16 [93]. Uliginosin B is a naturally occurring acylphloroglucinol that reduces pain, and its MoA appears to involve adenosine signaling [94].…”

Section: Pain Antidepressant Sleep and Other Behavioral Interventionmentioning

confidence: 99%

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

Reitman

2020

Cells

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Many ligands directly target adenosine receptors (ARs). Here we review the effects of noncanonical AR drugs on adenosinergic signaling. Non-AR mechanisms include raising adenosine levels by inhibiting adenosine transport (e.g., ticagrelor, ethanol, and cannabidiol), affecting intracellular metabolic pathways (e.g., methotrexate, nicotinamide riboside, salicylate, and 5-aminoimidazole-4-carboxamide riboside), or undetermined means (e.g., acupuncture). However, other compounds bind ARs in addition to their canonical ‘on-target’ activity (e.g., mefloquine). The strength of experimental support for an adenosine-related role in a drug’s effects varies widely. AR knockout mice are the ‘gold standard’ method for investigating an AR role, but few drugs have been tested on these mice. Given the interest in AR modulation for treatment of cancer, CNS, immune, metabolic, cardiovascular, and musculoskeletal conditions, it is informative to consider AR and non-AR adenosinergic effects of approved drugs and conventional treatments.

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Section: Pain Antidepressant Sleep and Other Behavioral Interventionmentioning

confidence: 99%

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

Reitman

2020

Cells

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“…Various herbal pain treatments are thought to involve AR signaling (Haematostaphis barteri, Ameyaw et al, 2016; Clinacanthus nutans, Zakaria et al, 2018). An antinociceptive and neuroprotective traditional Chinese medicine containing paeoniflorin, a monoterpene glucoside isolated from peony root, has allosteric A1AR activation as its putative mechanism of action (Gao et al, 2018). Uliginosin B is a naturally occurring acylphloroglucinol that reduces pain, and its MoA appears to involve adenosine signaling (Stolz et al, 2016).…”

Section: Pain Antidepressant Sleep and Other Behavioral Interventionmentioning

confidence: 99%

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

Reitman

2020

Preprint

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Many ligands directly target adenosine receptors (ARs). Here we review the effects on adenosinergic signaling of other drugs that are not typically identified as binding ARs. Non-AR mechanisms include raising adenosine levels by inhibiting adenosine transport (e.g. ticagrelor, ethanol, cannabidiol), affecting intracellular metabolic pathways (e.g. methotrexate, nicotinamide riboside, salicylate, AICA riboside), or undetermined means (e.g. acupuncture). Yet other compounds bind ARs, in addition to their canonical 'on-target' activity (e.g. mefloquine). The strength of experimental support varies widely. AR knockout mice are the 'gold standard' method for investigating an AR role, but few drugs have been tested in these mice. Given the interest in AR modulation for treatment of cancer, CNS, immune, metabolic, cardiovascular, and musculoskeletal conditions, it is informative to consider AR and non-AR adenosinergic effects of approved drugs and conventional treatments.

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“…The A 1 AR is prominently expressed in the central nervous system, spinal cord, heart and kidney. Agonists of A 1 AR could be useful as neuro‐ and cardioprotective agents as well as for the treatment of cardiac arrhythmias, pain, diabetes type‐2, reduction of lipolysis in adipose tissue and intraocular pressure in glaucoma (Cosimelli et al., ; Gao et al., ). In contrast, A 1 AR antagonists might be beneficial for the treatment of acute heart failure, asthma and chronic obstructive pulmonary disease (Brown, Spina, & Page, ; Gao et al., ; Kiesman, Elzein, & Zablocki, ).…”

Section: Introductionmentioning

confidence: 99%

“…Agonists of A 1 AR could be useful as neuro‐ and cardioprotective agents as well as for the treatment of cardiac arrhythmias, pain, diabetes type‐2, reduction of lipolysis in adipose tissue and intraocular pressure in glaucoma (Cosimelli et al., ; Gao et al., ). In contrast, A 1 AR antagonists might be beneficial for the treatment of acute heart failure, asthma and chronic obstructive pulmonary disease (Brown, Spina, & Page, ; Gao et al., ; Kiesman, Elzein, & Zablocki, ). The A 2A receptor antagonists are considered to be a potential non‐dopaminergic therapeutic approach for the treatment of neurodegenerative movement disorders such as Parkinson′s disease (PD) and Huntington′s disease, which resulted in the discovery and development of the xanthine derivative istradefylline as the first marketed selective A 2A AR antagonist as an adjunctive therapy of PD in Japan in 2013 (Pinna, ; Preti, Baraldi, Moorman, Borea, & Varani, ).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, a lot of efforts have been made to develop xanthine and non‐xanthine analogues with higher selectivity and affinity towards specific AR subtypes. Despite the continuous efforts made by various researchers, only few analogues with promising A 1 affinity have been identified so far (Borghini, Pietra, Leonardi, Giorgi, & Bianucci, ; Cosimelli et al., ; Gao et al., ; Kiesman et al., ; Romagnoli, Baraldi, Moorman, Borea, & Varani, ). In particular, 8‐amino‐2‐aryl‐[1,2,4]triazolo[1,5‐a]pyridine‐6‐carboxyl amides ( iii ) and isomeric 5‐amino‐2‐aryl‐[1,2,4]triazolo[1,5‐a]pyridine‐7‐carboxyl amide derivatives ( iv ) showed good affinity and selectivity towards hA 2A versus hA 1 ARs (Guba, Nettekoven, Püllmann, Riemer, & Schmitt, ).…”

Section: Introductionmentioning

confidence: 99%

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7‐Amino‐2‐aryl/hetero‐aryl‐5‐oxo‐5,8‐dihydro[1,2,4]triazolo[1,5‐a]pyridine‐6‐carbonitriles: Synthesis and adenosine receptor binding studies

et al. 2019

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A series of novel 7-amino-5-oxo-2-substituted-aryl/hetero-aryl-5, 8-dihydro[1,2,4] triazolo[1,5-a]pyridine-6-carbonitriles (4a-4t) was synthesized, characterized and evaluated for their binding affinity and selectivity towards hA 1 , hA 2A , hA 2B and hA 3 adenosine receptors (ARs). Compound 4a with a phenyl ring at 2-position of the triazolo moiety of the scaffold showed high affinity and selectivity for hA 1 AR (K i hA 1 = 0.076 μM, hA 2A = 25.6 μM and hA 3 > 100 μM). Introduction of various electron donating and withdrawing groups at different positions of the phenyl ring resulted in drastic reduction in affinity and selectivity towards all the ARs, except compound 4b with a 4-hydroxyphenyl group at 2-position. Interestingly, the replacement of the phenyl ring with a smaller heterocyclic thiophene ring (π excessive system) resulted in further improvement of affinity for hA 1 AR of compound 4t (K i hA 1 = 0.051 μM, hA 2A = 9.01 μM and hA 3 > 13.9 μM) while retaining the significant selectivity against all other AR subtypes similar to compound 4a. The encouraging results for compounds 4a and 4t indicate that substitution at 2-position of the scaffold with π-excessive systems other than thiophene may lead to even more potent and selective hA 1 AR antagonists. K E Y W O R D SA 1 adenosine receptors, adenosine receptor antagonists, cyanoacetic hydrazides, triazolopyridines

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A1 Adenosine Receptor Agonists, Antagonists, and Allosteric Modulators

Cited by 19 publications

References 197 publications

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

7‐Amino‐2‐aryl/hetero‐aryl‐5‐oxo‐5,8‐dihydro[1,2,4]triazolo[1,5‐a]pyridine‐6‐carbonitriles: Synthesis and adenosine receptor binding studies

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