Structure activity relationships of 5-HT2B and 5-HT2C serotonin receptor antagonists: N-6, C2 and 5 '-Modified (N)-methanocarba-adenosine derivatives

(N)-Methanocarba adenosine derivatives were structurally modified to target 5-HT2B serotonin receptors as antagonists, predominantly containing branched N-6-alkyl groups. N-6-Dicycloalkyl-methyl groups, including their asymmetric variations, as well as 2-iodo, were found to generally favor 5-HT2Rs, while only N-6-dicyclohexyl-methyl derivative 35 showed weak 5-HT2AR affinity (K-i 3.6 mu M). The highest 5-HT2BR affinities were Ki 11-23 nM (N-6-dicyclopropyl-methyl-2-iodo 11, 2-chloro-5'-deoxy-5'-methylthio 15 and N-6-((R)-cyclobuty-cyclopropyl-methyl)-2-iodo 43), and K-i 73 nM at 5-HT2CR 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-HT2BR (K-B 2-3 nM) and 5-HT2CR (K-B 79-328 nM) antagonists in a G(q)-mediated calcium flux assay, with 5-HT2BR functional selectivity ranging from 45-(48) to 113-fold (43). Substantial adenosine receptor (AR) affinity (K-i, A(1)AR < K-i, A(3)AR < K-i, A(2A)AR) was still present in this series, suggestive of dual acting compounds: 5-HT2B antagonist and A(1)AR agonist, potentially useful for treating chronic conditions (fibrosis; pain). Given its affinity (17 nM) and moderate 5-HT2BR binding selectivity (32-fold vs. 5-HT2CR, 4-fold vs. A(1)AR), 43 (MRS7925) could potentially be useful for anti-fibrotic therapy.