Rigidified A₃ Adenosine Receptor Agonists: 1-Deazaadenine Modification Maintains High in Vivo Efficacy

Abstract

Substitution of rigidified A 3 adenosine receptor (AR) agonists with a 2-((5-chlorothiophen-2-yl)ethynyl) or a 2-(4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl) group provides prolonged protection in a model of chronic neuropathic pain. These agonists contain a bicyclo[3.1.0]hexane ((N)-methanocarba) ring system in place of ribose, which adopts a receptor-preferred conformation. N 6 -Small alkyl derivatives were newly optimized for A 3 AR affinity and the effects of a 1-deaza-adenine modification probed. 1-Deaza-N 6 -ethyl alkyne 20 (MRS7144, K i 1.7 nM) and 1-aza N 6 -propyl alkyne 12 (MRS7154, K i 1.1 nM) were highly efficacious in vivo. Thus, the presence of N1 is not required for nanomolar binding affinity or potent, long-lasting functional activity. Docking of 1-deaza compounds to a receptor homology model confirmed a similar binding mode as previously reported 1-aza derivatives. This is the first demonstration in nonribose adenosine analogues that the 1-deaza modification can maintain high A 3 AR affinity, selectivity, and efficacy.

Scaffold Repurposing of Nucleosides (Adenosine Receptor Agonists): Enhanced Activity at the Human Dopamine and Norepinephrine Sodium Symporters

“…The 1-deaza modification ( 5a and 5b ) prevented enhancement of [ 3 H] 24 binding at hDAT, but not A 3 AR activation. 3,21 The corresponding 3-deaza 5′-methylamide 6 significantly enhanced [ 3 H] 24 binding at hDAT, but with less efficacy than 1 . Thus, the N1, but not N3, nitrogen atom was essential for interaction with hDAT.…”

Rigid Adenine Nucleoside Derivatives as Novel Modulators of the Human Sodium Symporters for Dopamine and Norepinephrine

“…Various sterically constrained adenine nucleoside derivatives (Supplemental Material; (Supplemental Table 1) (Table 1) have been synthesized and studied for their potent binding to the A 1 AR (compound 2) (Tosh et al, 2012b) or A 3 AR (compounds 1, 3-9, 14-19, 21-28, 31, and 32) (Tosh et al, 2012a(Tosh et al, , 2015a. Many of these A 3 AR agonists reduce chronic neuropathic pain in a phenotypic screen, and the AR binding affinities of the previously reported nucleosides are provided (Supplemental Material; (Supplemental Table 2).…”

“…Based on these findings, additional compounds (10-13, 20, 29, and 30) were synthesized to explore the structure-activity relationship (SAR) at these three transporters. The synthetic procedures and the AR activity of the latter set of compounds are reported elsewhere (Tosh et al, 2015a).…”

Metabolic mapping of A3 adenosine receptor agonist MRS5980

“…from the market and a decrease of new chemical entities (NCEs) introduced into the market [13]. In preclinical efficacy testing, in the chronic constriction injury (CCI, sciatic nerve) model in mice, the ED 50 value of MRS5980 at its peak effect following oral administration was 0.34 mg/kg (0.73 mol/kg; n=5) [6]. On a molar dose basis, this is more potent than morphine, amitriptyline or gabapentin in the same model [14].…”

“…), and development of A 3 AR selective agonists as drug candidates has been a major goal to treat these diseases [6,7]. (1 S ,2 R ,3 S ,4 R ,5 S )-4-(2-((5-Chlorothiophen-2-yl)ethynyl)-6-(methylamino)-9 H -purin-9-yl)-2,3-dihydroxy- N -methylbicyclo[3.1.0]hexane-1-carboxamide (MRS5980) is a recently developed A 3 AR selective agonist that contains multiple receptor affinity- and selectivity-enhancing modifications [8].…”