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