Structure activity relationships of 5-HT2B and 5-HT2C serotonin receptor antagonists: N6, C2 and 5'-Modified (N)-methanocarba-adenosine derivatives

(N)-Methanocarba adenosine derivatives were structurally modified to target 5-HT_2B serotonin receptors as antagonists, predominantly containing branched N⁶-alkyl groups. N⁶-Dicycloalkyl-methyl groups, including their asymmetric variations, as well as 2-iodo, were found to generally favor 5-HT₂Rs, while only N⁶-dicyclohexyl-methyl derivative 35 showed weak 5-HT_2AR affinity (K_i 3.6 μM). The highest 5-HT_2BR affinities were K_i 11-23 nM (N⁶-dicyclopropyl-methyl-2-iodo 11, 2-chloro-5'-deoxy-5'-methylthio 15 and N⁶-((R)-cyclobuty-cyclopropyl-methyl)-2-iodo 43), and K_i 73 nM at 5-HT_2CR 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-HT_2BR (K_B 2-3 nM) and 5-HT_2CR (K_B 79-328 nM) antagonists in a G_q-mediated calcium flux assay, with 5-HT_2BR functional selectivity ranging from 45- (48) to 113-fold (43). Substantial Adenosine Receptor (AR) affinity (K_i, A₁AR < K_i, A₃AR < K_i, A_2AAR) was still present in this series, suggestive of dual acting compounds: 5-HT_2B antagonist and A₁AR agonist, potentially useful for treating chronic conditions (fibrosis; pain). Given its affinity (17 nM) and moderate 5-HT_2BR binding selectivity (32-fold vs. 5-HT_2CR, 4-fold vs. A₁AR), 43 (MRS7925) could potentially be useful for anti-fibrotic therapy.

Adenosine receptor; Functional antagonism; G protein-coupled receptor; Methanocarba; Nucleosides; Radioligand binding; Scaffold repurposing; Serotonin 5-HT(2B) receptor; Serotonin receptor; Structure activity relationship.