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A(1) adenosine receptor (AR) agonists display antiischemic and antiepileptic neuroprotective activity, but peripheral cardiovascular side effects impeded their development. SAR study of N(6)-cycloalkylmethyl 4'-truncated (N)-methanocarba-adenosines identified 10 (MRS5474, N(6)-dicyclopropylmethyl, K(i) = 47.9 nM) as a moderately A(1)AR-selective full(More)
(N)-Methanocarba adenosine 5'-methyluronamides containing known A(3) AR (adenosine receptor)-enhancing modifications, i.e., 2-(arylethynyl)adenine and N(6)-methyl or N(6)-(3-substituted-benzyl), were nanomolar full agonists of human (h) A(3)AR and highly selective (K(i) ∼0.6 nM, N(6)-methyl 2-(halophenylethynyl) analogues 13 and 14). Combined(More)
(N)-Methanocarba(bicyclo[3.1.0]hexane)adenosine derivatives were probed for sites of charged sulfonate substitution, which precludes diffusion across biological membranes, e.g., blood-brain barrier. Molecular modeling predicted that sulfonate groups on C2-phenylethynyl substituents would provide high affinity at both mouse (m) and human (h) A3 adenosine(More)
We previously synthesized a series of potent and selective A(3) adenosine receptor (AR) agonists (North-methanocarba nucleoside 5'-uronamides) containing dialkyne groups on extended adenine C2 substituents. We coupled the distal alkyne of a 2-octadiynyl nucleoside by Cu(I)-catalyzed "click" chemistry to azide-derivatized G4 (fourth-generation) PAMAM(More)
More than 1.5 billion people worldwide suffer from chronic pain, yet current treatment strategies often lack efficacy or have deleterious side effects in patients. Adenosine is an inhibitory neuromodulator that was previously thought to mediate antinociception through the A1 and A2A receptor subtypes. We have since demonstrated that A3AR agonists have(More)
Truncated D-4'-thioadenosine derivatives lacking the 4'-hydroxymethylene moiety were synthesized starting from D-mannose, using cyclization to the 4-thiosugar and one-step conversion of the diol to the acetate as key steps. At the human A3 adenosine receptor (AR), N6-substituted purine analogues bound potently and selectively and acted as antagonists in a(More)
Clinical management of chronic neuropathic pain is limited by marginal effectiveness and unacceptable side effects of current drugs. We demonstrate A(3) adenosine receptor (A(3)AR) agonism as a new target-based therapeutic strategy. The development of mechanoallodynia in a well-characterized mouse model of neuropathic pain following chronic constriction(More)
Various fluorescent nucleoside agonists of the A3 adenosine receptor (AR) were compared as high affinity probes using radioligands and flow cytometry (FCM). They contained a fluorophore linked through the C2 or N(6) position and rigid A3AR-enhancing (N)-methanocarba modification. A hydrophobic C2-(1-pyrenyl) derivative MRS5704 bound nonselectively.(More)
We reported that 2-(3,4-difluorophenylethynyl)-N 6-3-chlorobenzyl (N)-methanocarba adenosine derivative 1 (MRS5698) binds selectively to human and mouse A3 adenosine receptors (A3ARs, K i 3 nM). It is becoming an important pharmacological tool for defining A3AR effects and is orally active in a chronic neuropathic pain model. Here, we introduce a new(More)
We studied patterns of off-target receptor interactions, mostly at G protein-coupled receptors (GPCRs) in the µM range, of nucleoside derivatives that are highly engineered for nM interaction with adenosine receptors (ARs). Because of the considerable interest of using AR ligands for treating diseases of the CNS, we used the Psychoactive Drug Screening(More)