(N)-Methanocarba adenosine derivatives were structurally modified to target 5-HT serotonin receptors as antagonists, predominantly containing branched N-alkyl groups. N-Dicycloalkyl-methyl groups, including their asymmetric variations, as well as 2-iodo, were found to generally favor 5-HTRs, while only N-dicyclohexyl-methyl derivative 35 showed weak 5-HTR affinity (K 3.6 μM). The highest 5-HTR affinities were K 11-23 nM (N-dicyclopropyl-methyl-2-iodo 11, 2-chloro-5′-deoxy-5′-methylthio 15 and N-((R)-cyclobuty-cyclopropyl-methyl)-2-iodo 43), and K 73 nM at 5-HTR for 36. Direct comparison of adenine ribosides and their corresponding rigid (N)-methanocarba derivatives (cf. 51 and MRS8099 45) indicated a multifold affinity enhancement with the bicyclic ring system. Compounds 43, 45 and 48 were functional 5-HTR (K 2-3 nM) and 5-HTR (K 79-328 nM) antagonists in a G-mediated calcium flux assay, with 5-HTR functional selectivity ranging from 45- (48) to 113-fold (43). Substantial adenosine receptor (AR) affinity (K, AAR < K, AAR < K, AAR) was still present in this series, suggestive of dual acting compounds: 5-HT antagonist and AAR agonist, potentially useful for treating chronic conditions (fibrosis; pain). Given its affinity (17 nM) and moderate 5-HTR binding selectivity (32-fold vs. 5-HTR, 4-fold vs. AAR), 43 (MRS7925) could potentially be useful for anti-fibrotic therapy.