Direct Comparison of (N)-Methanocarba and Ribose-Containing 2-Arylalkynyladenosine Derivatives As A Receptor Agonists

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2020 Oct 16

PMID 33062176

Citations 17

Authors

Dilip K Tosh

Veronica Salmaso

Harsha Rao

Ryan Campbell

Amelia Bitant

Zhan-Guo Gao

John A Auchampach

Kenneth A Jacobson

Affiliations

Soon will be listed here.

Abstract

A side-by-side pharmacological comparison of ribose and (N)-methanocarba (bicyclo[3.1.0]hexane) nucleosides as AAR agonists indicated that the bicyclic pseudoribose ring constraint provided higher affinity/selectivity at human and mouse AAR. The mean affinity enhancement for 5 pairs of 5'-methylamides was 11-fold at hAAR and 42-fold at mAAR. Novel C2-(5-fluorothien-2-ylethynyl) substitution enhanced affinity in the methanocarba but not ribose series, with highly hAAR-selective (MRS7334) displaying K 280 pM and favorable pharmacokinetics and off-target activity profile. Molecular dynamics comparison of and its corresponding riboside suggested a qualitative entropic advantage of in hAAR binding. The 5-F substitution tended to increase hAAR affinity (cf. 5-Cl) for methanocarba but not ribose derivatives. A representative methanocarba agonist was shown to interact potently exclusively with AAR, among 240 GPCRs and 466 kinases. Thus, despite added synthetic difficulty, the (N)-methanocarba modification has distinct advantages for AAR agonists, which have translational potential for chronic disease treatment.

Citing Articles

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2-Substituted (N)-Methanocarba A Adenosine Receptor Agonists: In Silico, In Vitro, and In Vivo Characterization.

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

Tosh D, Calkins M, Ivancich M, Bock H, Campbell R, Lewicki S Eur J Med Chem. 2023; 259:115691.

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