Structure activity relationships of 5-HT(2B) and 5-HT(2C) serotonin receptor antagonists: N(6), 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 N(6)-alkyl groups. N(6)-Dicycloalkyl-methyl groups, including their asymmetric variations, as well as 2-iodo, were found to generally favor 5-HT(2)Rs, while only N(6)-dicyclohexyl-methyl derivative 35 showed weak 5-HT(2A)R affinity (K(i) 3.6 μM). The highest 5-HT(2B)R affinities were K(i) 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-HT(2C)R 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(2B)R (K(B) 2-3 nM) and 5-HT(2C)R (K(B) 79-328 nM) antagonists in a G(q)-mediated calcium flux assay, with 5-HT(2B)R 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-HT(2B) antagonist and A(1)AR agonist, potentially useful for treating chronic conditions (fibrosis; pain). Given its affinity (17 nM) and moderate 5-HT(2B)R binding selectivity (32-fold vs. 5-HT(2C)R, 4-fold vs. A(1)AR), 43 (MRS7925) could potentially be useful for anti-fibrotic therapy.