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

Abstract

A1 adenosine receptor (AR) agonists are neuroprotective, cardioprotective, and anxiolytic. (N)-Methanocarba adenine nucleosides designed to bind to human A1AR were truncated to eliminate 5′-CH2OH. This modification previously converted A3AR agonists into antagonists, but the comparable effect at A1AR is unknown. In comparison to ribosides, affinity at the A1AR was less well preserved than at the A3AR, although a few derivatives were moderately A1AR selective, notably full agonist 21 (N6-dicyclopropylmethyl, Ki 47.9 nM). Thus, at the A1AR recognition elements for nucleoside binding depend more on 5′region interactions, and in their absence A3AR 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 A1 but not A3AR. The derivatives ranged from partial to full agonists in A1AR-mediated adenylate cyclase inhibition. Truncated derivatives have more drug-like physical properties than other A1AR agonists; this approach is appealing for preclinical development.

Exploring the Role of N6-Substituents in Potent Dual Acting 5′-C-Ethyltetrazolyladenosine Derivatives: Synthesis, Binding, Functional Assays, and Antinociceptive Effects in Mice

“…The hA 1 AR homology model was built using as template the crystal structure of the human A 2A AR cocrystallized with the agonist UK-432097 (PDB code 3QAK). 21 The 3QAK structure was also selected as a template for the entire A 3 AR structure except for the extracellular terminus of TM2 (residues from V63 to S73) and EL1 (residues from L74 to Y81). The X-ray structure of the h β 2 adrenergic receptor in complex with the G s protein (PDB code 3SN6), 48 after superimposition with the hA 2A AR crystal structure, was set as template for the extracellular terminus of TM2.…”

Methanocarba ring as a ribose modification in ligands of G protein-coupled purine and pyrimidine receptors: synthetic approaches

“…The truncated (N)-methanocarba purine analogues 99 (MRS5474) and 100 (MRS5719) showed selectivity as A 1 AR full agonist and partial agonist, respectively. 20 The 2-phenylalkynyl derivative 21 in the truncated series showed selectivity as an A 3 AR antagonist, 19,21 and the related 5′-methyluronamides 101 (MRS5697) and 102 (MRS5698) were highly selective agonists at both human and mouse A 3 ARs. 18 …”

“…21 Extensive modification of this class of molecules provided various lead molecules to achieve selectivity for either the A 1 AR or the A 3 AR. 19,20 The cyclopentone derivative 22b was synthesized from D-ribose 22a in six steps (Scheme 3c), 22 a and the glycosyl sugar 22c was formed upon the stereoselective reduction of 22b by sodium borohydride in the presence of cerium(III) chloride followed by a Simmons–Smith cyclopropanation of the resulting alcohol. An alternate synthesis of intermediate 22b involving ring closing metathesis reaction and starting with D-isoascorbic acid had a lower yield and a volatile intermediate.…”

“…22 b Mitsunobu condensation of the compound 22c with various purine bases gave the intermediates of the general formula 23 , which upon amination with various amines at the N 6 position, and subsequent acid hydrolysis provided truncated methanocarba nucleosides 24 . 19,20 Alternately, group R of 24 was an arylethynyl substitution, which despite its steric bulk was recognized at the A 3 AR, especially with small R 1 groups. 19 …”

Adenosine-associated delivery systems

“…For example, ligand of AR antagonists are capable to treat sleep apnea, cancer pain, asthma (Ecke et al, 2008, Guo et al, 2002). A 1 agonists have been shown to be effective for Glaucoma, atrial fibrillation, and paroxysmal supraventricular tachycardia (Tosh et al, 2011, Fredholm et al, 2011). A 2A agonists can inhibit the release of pro-inflammatory cytokines and have anti-inflammatory and anti-ischemic effects (Wang et al, 2010).…”