<i>N</i>-Substituted Adenosines as Novel Neuroprotective A<sub>1</sub> Agonists with Diminished Hypotensive Effects

Knutsen, Lars J. S.; Lau, Jesper; Petersen, H; Thomsen, C.; Weis, Ján; Shalmi, Michael; Judge, Martin E.; Hansen, and A. J.; Sheardown, Malcolm J.

doi:10.1021/jm960682u

Cited by 66 publications

(62 citation statements)

References 69 publications

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“…ADAC, an A 1 AR agonist, was potent in cerebroprotection in a model of global ischaemia in gerbils 134 . The A 1 AR agonist NNC-21-0136 was neuroprotective in both global and focal rodent ischaemia models and had diminished cardiovascular effects in rats compared with reference A 1 AR agonists, such as CPA 135 . However, it was recently shown that deletion of the gene that encodes the A 1 AR does not alter neuronal damage that occurs after ischaemia in vivo or in vitro 136 , although A 1 ARs have been shown to be relevant to hypoxia protection in newborn mice 137 .…”

Section: Ischaemia and Neuroprotectionmentioning

confidence: 93%

Adenosine receptors as therapeutic targets

Jacobson

Gao

2006

Nat Rev Drug Discov

1,273

1,361

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Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer.

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Section: Ischaemia and Neuroprotectionmentioning

confidence: 93%

Adenosine receptors as therapeutic targets

Jacobson

Gao

2006

Nat Rev Drug Discov

1,273

1,361

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“…Branching of the alkyl groups in N 6 -substituted adenosines has been well studied at the A 1 AR and A 2A AR. [13][14][15][16] At the hA 3 AR, a moderate degree of stereoselectivity of binding was observed for introduction of a methyl group in the R configuration at either the 1-(28 compared with 29) or 2-(30 compared with 31) position.…”

Section: Biological Activitymentioning

confidence: 99%

“…One of the analogues, containing a 3-nitro group (15), was resolved into pure diastereomers with HPLC, using the chiral column Chiralpak AD. The assignment of absolute configuration was done by analogy to the unsubstituted phenylcyclopropyl derivatives as standards.…”

Section: Introductionmentioning

confidence: 99%

Exploring distal regions of the A3 adenosine receptor binding site: sterically constrained N6-(2-phenylethyl)adenosine derivatives as potent ligands

Tchilibon

Kim

Gao

et al. 2004

Bioorganic & Medicinal Chemistry

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We synthesized phenyl ring-substituted analogues of N 6 -(1S,2R)-(2-phenyl-1-cyclopropyl)adenosine, which is highly potent in binding to the human A 3 AR with a K i value of 0.63 nM. The effects of these structural changes on affinity at human and rat adenosine receptors and on intrinsic efficacy at the hA 3 AR were measured. A 3-nitrophenyl analogue was resolved chromatographically into pure diastereomers, which displayed 10-fold stereoselectivity in A 3 AR binding in favor of the 1S,2R isomer. A molecular model defined a hydrophobic region (Phe168) in the putative A 3 AR binding site around the phenyl moiety. A heteroaromatic group (3-thienyl) could substitute for the phenyl moiety with retention of high affinity of A 3 AR binding. Other related N 6 -substituted adenosine derivatives were included for comparison. Although the N 6 -(2-phenyl-1-cyclopropyl) derivatives were full A 3 AR agonists, several other derivatives had greatly reduced efficacy. N 6 -Cyclopropyladenosine was an A 3 AR antagonist, and adding either one or two phenyl rings at the 2-position of the cyclopropyl moiety restored efficacy. N 6 -(2,2-Diphenylethyl)adenosine was an A 3 AR antagonist, and either adding a bond between the two phenyl rings (N 6 -9-fluorenylmethyl) or shortening the ethyl moiety (N 6 -diphenylmethyl) restored efficacy. A QSAR study of the N 6 region provided a model that was complementary to the putative A 3 AR binding site in a rhodopsin-based homology model. Thus, a new series of highaffinity A 3 AR agonists and related nucleoside antagonists was explored through both empirical and theoretical approaches.

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“…The selective modulation of A1AR may also have neuroprotective effects as adenosine can counteract the toxic effects of glutamate-mediated excitotoxicity (141). Indeed, several A1AR agonists display neuroprotective properties in animal models of cerebral ischemia (142,143,144). In addition, stimulation of A3AR is also neuroprotective in a gerbil model of ischemia (145).…”

mentioning

confidence: 99%

Regulation of neurite outgrowth by Gi/o signaling pathways

Kenneth¹

2008

Front Biosci

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Neurogenesis is a long and winding journey. A neural progenitor cell migrates long distances, differentiates by forming a single axon and multiple dendrites, undergoes maturation, and ultimately survives. The initial formation of neurites during neuronal differentiation, commonly referred to as "neurite outgrowth," can be induced by a large repertoire of signals that stimulate an array of receptors and downstream signaling pathways. The G i/o family of heterotrimeric Gproteins are abundantly expressed in the brain and enriched at neuronal growth cones. Recent evidence has uncovered several G i/o -coupled receptors that induce neurite outgrowth and has begun to elucidate the underlying molecular mechanisms. Emerging data suggests that signals from several G i/o -coupled receptors converge at the transcription factor STAT3 to regulate neurite outgrowth and at Rac1 and Cdc42 to regulate cytoskeletal reorganization. Physiologically, signaling through G i/o -coupled cannabinoid receptors is critical for proper central nervous system development. As the mechanisms by which G i/o -coupled receptors regulate neurite outgrowth are clarified, it is becoming evident that modulating signals from G i/o and their receptors has great potential for the treatment of neurodegenerative diseases. KeywordsG-protein; Neurite Outgrowth; Cell Signaling; Cannabinoid Receptor; Neurodegeneration; Review INTRODUCTIONNeuronal differentiation is a complex process that integrates many signals to drive electrophysiological, morphological, and transcriptional changes (1,2,3,4). This process is characterized by the initial formation of immature neurites, commonly referred to as "neurite outgrowth." The neurites then further develop into a single axon and multiple dendrites, followed by maturation of the neuron and the formation of dendritic spines (1). Many signals at the cell surface are integrated to shape axonal and dendritic outgrowths as well as their directionality and maturation (5,6,7,8). Not surprisingly, neurite outgrowth is precisely regulated due to its importance in the proper development of the organism. During neurite outgrowth, signals at the membrane are transduced to a large repertoire of enzymes to ultimately trigger changes in gene transcription in the nucleus. In addition, the signals produce vast changes in the actin and microtubule cytoskeletal networks in order to generate and stabilize the growing neurites (1,8 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptA diverse array of ligands including neurotrophins, cytokines, hormones, and neurotransmitters can stimulate neurite outgrowth upon binding to their cognate receptors (5,7,9,10,11,12,13,14). Heterotrimeric guanine nucleotide-binding proteins (G-proteins) are one of the most widely used signal transduction systems in mammals, and signaling through the G i/o family of G-proteins regulates neurite outgrowth. In cortical neurons, dopaminemediated stimulation of the D2 dopamine receptor can induce axonal neurite elongation (10). Similarl...

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N-Substituted Adenosines as Novel Neuroprotective A₁ Agonists with Diminished Hypotensive Effects

Cited by 66 publications

References 69 publications

Adenosine receptors as therapeutic targets

Adenosine receptors as therapeutic targets

Exploring distal regions of the A3 adenosine receptor binding site: sterically constrained N6-(2-phenylethyl)adenosine derivatives as potent ligands

Regulation of neurite outgrowth by Gi/o signaling pathways

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N-Substituted Adenosines as Novel Neuroprotective A1 Agonists with Diminished Hypotensive Effects

Cited by 66 publications

References 69 publications

Adenosine receptors as therapeutic targets

Adenosine receptors as therapeutic targets

Exploring distal regions of the A3 adenosine receptor binding site: sterically constrained N6-(2-phenylethyl)adenosine derivatives as potent ligands

Regulation of neurite outgrowth by Gi/o signaling pathways

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N-Substituted Adenosines as Novel Neuroprotective A₁ Agonists with Diminished Hypotensive Effects