Design and in Vivo Characterization of A 1 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 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.