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

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

  • Eur J Med Chem. 2023 Nov 5;259:115691. doi: 10.1016/j.ejmech.2023.115691.
Dilip K Tosh 1 Maggie M Calkins 2 Marko S Ivancich 2 Hailey A Bock 2 Ryan G Campbell 1 Sarah A Lewicki 1 Eric Chen 1 Zhan-Guo Gao 1 John D McCorvy 2 Kenneth A Jacobson 3
Affiliations

Affiliations

  • 1 Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
  • 2 Medical College of Wisconsin, Department of Cell Biology, Neurobiology, and Anatomy, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
  • 3 Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA. Electronic address: kennethj@niddk.nih.gov.
Abstract

(N)-Methanocarba adenosine derivatives were structurally modified to target 5-HT2B 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-HT2AR affinity (Ki 3.6 μM). The highest 5-HT2BR affinities were Ki 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 Ki 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 (KB 2-3 nM) and 5-HT2CR (KB 79-328 nM) antagonists in a Gq-mediated calcium flux assay, with 5-HT2BR functional selectivity ranging from 45- (48) to 113-fold (43). Substantial Adenosine Receptor (AR) affinity (Ki, A1AR < Ki, A3AR < Ki, A2AAR) was still present in this series, suggestive of dual acting compounds: 5-HT2B antagonist and A1AR 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. A1AR), 43 (MRS7925) could potentially be useful for anti-fibrotic therapy.

Keywords

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

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