2015
DOI: 10.1021/acsmedchemlett.5b00150
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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-D… Show more

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Cited by 22 publications
(67 citation statements)
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“…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.…”
Section: Resultsmentioning
confidence: 99%
“…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.…”
Section: Resultsmentioning
confidence: 99%
“…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).…”
Section: Resultsmentioning
confidence: 99%
“…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).…”
Section: Resultsmentioning
confidence: 99%
“…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].…”
Section: Discussionmentioning
confidence: 99%
“…), 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].…”
Section: Introductionmentioning
confidence: 99%