(N)-Methanocarba ([3.1.0]bicyclohexyl) adenosines and corresponding ribosides were synthesized to identify novel A 1 adenosine receptor (A 1 AR) agonists for CNS or peripheral applications. Human and mouse AR binding was determined to assess the constrained ring system's A 1 AR compatibility. N 6 -Dicyclobutylmethyl ribose agonist (9, MRS7469, >2000-fold selective for A 1 AR) and known truncated N 6 -dicyclopropylmethyl methanocarba 7 (MRS5474) were drug-like. The pure diastereoisomer of known riboside 4 displayed high hA 1 AR selectivity. Methanocarba modification reduced A 1 AR selectivity of N 6 -dicyclopropylmethyl and endo-norbornyladenosines but increased ribavirin selectivity. Most analogues tested (ip) were inactive or weak in inducing mouse hypothermia, despite mA 1 AR full agonism and variable mA 3 AR efficacy, but strong hypothermia by 9 depended on A 1 AR, which reflects CNS activity (determined using A 1 AR or A 3 AR null mice). Conserved hA 1 AR interactions were preserved in modeling of 9 and methanocarba equivalent 24 (∼400-fold A 1 AR-selective). Thus, we identified, and characterized in vivo, ribose and methanocarba nucleosides, including with A 1 AR-enhancing N 6 -dicyclobutylmethyl-adenine and 1,2,4-triazole-3-carboxamide (40, MRS7451) nucleobases.

Design and in Vivo Characterization of A 1 Adenosine Receptor Agonists in the Native Ribose and Conformationally Constrained (N)-Methanocarba Series

Ciancetta A.;
2019

Abstract

(N)-Methanocarba ([3.1.0]bicyclohexyl) adenosines and corresponding ribosides were synthesized to identify novel A 1 adenosine receptor (A 1 AR) agonists for CNS or peripheral applications. Human and mouse AR binding was determined to assess the constrained ring system's A 1 AR compatibility. N 6 -Dicyclobutylmethyl ribose agonist (9, MRS7469, >2000-fold selective for A 1 AR) and known truncated N 6 -dicyclopropylmethyl methanocarba 7 (MRS5474) were drug-like. The pure diastereoisomer of known riboside 4 displayed high hA 1 AR selectivity. Methanocarba modification reduced A 1 AR selectivity of N 6 -dicyclopropylmethyl and endo-norbornyladenosines but increased ribavirin selectivity. Most analogues tested (ip) were inactive or weak in inducing mouse hypothermia, despite mA 1 AR full agonism and variable mA 3 AR efficacy, but strong hypothermia by 9 depended on A 1 AR, which reflects CNS activity (determined using A 1 AR or A 3 AR null mice). Conserved hA 1 AR interactions were preserved in modeling of 9 and methanocarba equivalent 24 (∼400-fold A 1 AR-selective). Thus, we identified, and characterized in vivo, ribose and methanocarba nucleosides, including with A 1 AR-enhancing N 6 -dicyclobutylmethyl-adenine and 1,2,4-triazole-3-carboxamide (40, MRS7451) nucleobases.
2019
Tosh, D. K.; Rao, H.; Bitant, A.; Salmaso, V.; Mannes, P.; Lieberman, D. I.; Vaughan, K. L.; Mattison, J. A.; Rothwell, A. C.; Auchampach, J. A.; Ciancetta, A.; Liu, N.; Cui, Z.; Gao, Z. -G.; Reitman, M. L.; Gavrilova, O.; Jacobson, K. A.
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