Design and in Vivo Characterization of A1 Adenosine Receptor Agonists in the Native Ribose and Conformationally Constrained (N)-Methanocarba Series

(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 AIAR or A(3)AR null mice). Conserved hA(1)AR interactions were preserved in modeling of 9 and methanocarba equivalent 24 (similar to 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.