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Extended N(6) substitution of rigid C2-arylethynyl nucleosides for exploring the role of extracellular loops in ligand recognition at the A3 adenosine receptor.

ABSTRACT: 2-Arylethynyl-(N)-methanocarba adenosine 5'-methyluronamides containing rigid N(6)-(trans-2-phenylcyclopropyl) and 2-phenylethynyl groups were synthesized as agonists for probing structural features of the A3 adenosine receptor (AR). Radioligand binding confirmed A3AR selectivity and N(6)-1S,2R stereoselectivity for one diastereomeric pair. The environment of receptor-bound, conformationally constrained N(6) groups was explored by docking to an A3AR homology model, indicating specific hydrophobic interactions with the second extracellular loop able to modulate the affinity profile. 2-Pyridylethynyl derivative 18 was administered orally in mice to reduce chronic neuropathic pain in the chronic constriction injury model.

SUBMITTER: Tosh DK

PROVIDER: S-EPMC4158450 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Extended N(6) substitution of rigid C2-arylethynyl nucleosides for exploring the role of extracellular loops in ligand recognition at the A3 adenosine receptor.

Tosh Dilip K DK Paoletta Silvia S Chen Zhoumou Z Moss Steven M SM Gao Zhan-Guo ZG Salvemini Daniela D Jacobson Kenneth A KA

Bioorganic & medicinal chemistry letters 20140611 15

2-Arylethynyl-(N)-methanocarba adenosine 5'-methyluronamides containing rigid N(6)-(trans-2-phenylcyclopropyl) and 2-phenylethynyl groups were synthesized as agonists for probing structural features of the A3 adenosine receptor (AR). Radioligand binding confirmed A3AR selectivity and N(6)-1S,2R stereoselectivity for one diastereomeric pair. The environment of receptor-bound, conformationally constrained N(6) groups was explored by docking to an A3AR homology model, indicating specific hydrophobi ...[more]

PMID: 24969016

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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.

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