Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A₃ Adenosine Receptor Agonists

Abstract

Purine (N)-methanocarba-5′-N-alkyluronamidoriboside A3 adenosine receptor (A3AR) agonists lacking an exocyclic amine resulted from an unexpected reaction during a Sonogashira coupling and subsequent aminolysis. Because the initial C6-Me and C6-styryl derivatives had unexpectedly high A3AR affinity, other rigid nucleoside analogues lacking an exocyclic amine were prepared. Of these, the C6-Me-(2-phenylethynyl) and C2-(5-chlorothienylethynyl) analogues were particularly potent, with human A3AR Ki values of 6 and 42 nM, respectively. Additionally, the C2-(5-chlorothienyl)-6-H analogue was potent and selective at A3AR (MRS7220, Ki 60 nM) and also completely reversed mouse sciatic nerve mechanoallodynia (in vivo, 3 μmol/kg, po). The lack of a C6 H-bond donor while maintaining A3AR affinity and efficacy could be rationalized by homology modeling and docking of these hypermodified nucleosides. The modeling suggests that a suitable combination of stabilizing features can partially compensate for the lack of an exocyclic amine, an otherwise important contributor to recognition in the A3AR binding site.

A3 Adenosine Receptors as Modulators of Inflammation: From Medicinal Chemistry to Therapy

“…The surprising finding that substitution of the exocylic NH of adenine with H or CH 3 in MRS5919 32 allowed full activation of the A 3 AR emphasized that the loss of otherwise important recognition elements in a ligand can be compensated by other affinity enhancing moieties on the nucleoside . Moreover, the ribose moiety is the main effector of receptor activation, while adenine modifications tend to change the subtype selectivity but usually do not have a major effect on the agonist efficacy.…”

“…133 The surprising finding that substitution of the exocylic NH of adenine with H or CH 3 in MRS5919 32 allowed full activation of the A 3 AR emphasized that the loss of otherwise important recognition elements in a ligand can be compensated by other affinity enhancing moieties on the nucleoside. 134 Moreover, the ribose moiety is the main effector of receptor activation, while adenine modifications tend to change the subtype selectivity but usually do not have a major effect on the agonist efficacy. However, there are exceptions to the above generalization, including various N 6 substituents and C2 substituents that produce partial agonism or antagonism at the A 3 AR, as has been summarized, 135 and nucleoside derivatives with reduced efficacy are discussed below.…”

Ferulic acid dimer as a non-opioid therapeutic for acute pain

“…The conformation adopted by FAD- A 3 AR complex revealed several interactions in the present model, and this is in good agreement with the data published previously. 34 , 35 Homology binding to other adenosine receptors was not as evident as with A 3 AR .…”

Probing structure-activity relationship in β-arrestin2 recruitment of diversely substituted adenosine derivatives

“…The same residue accepts a H-bond from the 6-amino group (bidentate ligand coordination). However, it was shown that a suitable combination of stabilizing interactions in these kind of hypermodified A 3 AR-selective ligands can partially compensate for the lack of an exocyclic amine, an otherwise important contributor to recognition in the A3AR binding site [32]. This is demonstrated by the sustained A3AR activity of MRS7195 and MRS7220 in cAMP signalling as well as in βarr2 recruitment (Table 2; Figure 2F; Figure 3, mustard curves), although MRS7220 has a substantially reduced Emax and logEC 50 compared to those of other (N)-methanocarba 5′-methyluronamide derivatives.…”