4.5 Article

Truncated (N)-Methanocarba Nucleosides as A1 Adenosine Receptor Agonists and Partial Agonists: Overcoming Lack of a Recognition Element

期刊

ACS MEDICINAL CHEMISTRY LETTERS
卷 2, 期 8, 页码 626-631

出版社

AMER CHEMICAL SOC
DOI: 10.1021/ml200114q

关键词

G protein-coupled receptor; purines; molecular modeling; radioligand binding; adenylate cyclase

资金

  1. NIH, NIDDK

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A(1) adenosine receptor (AR) agonists are neuroprotective, cardioprotective, and anxiolytic. (N)-Methanocarba adenine nucleosides designed to bind to human A(1)AR were truncated to eliminate 5'-CH2OH. This modification previously converted A(3)AR agonists into antagonists, but the comparable effect at A(1)AR is unknown. In comparison to ribosides, affinity at the A(1)AR was less well preserved than that at the A(3)AR, although a few derivatives were moderately A(1)AR selective, notably full agonist 21 (N-6-dicyclopropyl-methyl, K-i 47.9 nM). Thus, at the A(1)AR, recognition elements for nucleoside binding depend more on 5' region interactions, and in their absence, A(3)AR selectivity predominates. Based on the recently reported agonist-bound AR structure, this difference between subtypes likely correlates with an essential His residue in transmembrane domain 6 of A(1) but not A(3)AR The derivatives ranged from partial to full agonists in A(1)AR-mediated adenylate cyclase inhibition. Truncated derivatives have more druglike physical properties than other A(1)AR agonists; this approach is appealing for preclinical development.

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