Dataset Information

Tetrahydroimidazo[1,2-a]pyrazine Derivatives: Synthesis and Evaluation as G?q -Protein Ligands.

ABSTRACT: The 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine derivative BIM-46174 and its dimeric form BIM-46187 (1) are heterocyclized dipeptides that belong to the very few cell-permeable compounds known to preferentially silence G?q proteins. To explore the chemical space of G?q inhibitors of the BIM chemotype, a combinatorial approach was conducted towards a library of BIM molecules. This library was evaluated in a second messenger-based fluorescence assay to analyze the activity of G?q proteins through the determination of intracellular myo-inositol 1-phosphate. Structure-activity relationships were deduced and structural requirements for biological activity obtained, which were (i)?a redox reactive thiol/disulfane substructure, (ii)?an N-terminal basic amino group, (iii)?a cyclohexylalanine moiety, and (iv)?a bicyclic skeleton. Active compounds exhibited cellular toxicity, which was investigated in detail for the prototypical inhibitor 1. This compound affects the structural cytoskeletal dynamics in a G?q/11 -independent manner.

SUBMITTER: Kuppers J

PROVIDER: S-EPMC7590114 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tetrahydroimidazo[1,2-a]pyrazine Derivatives: Synthesis and Evaluation as Gαq -Protein Ligands.

Küppers Jim J Benkel Tobias T Annala Suvi S Kimura Kenichi K Reinelt Lisa L Fleischmann Bernd K BK Kostenis Evi E Gütschow Michael M

Chemistry (Weinheim an der Bergstrasse, Germany) 20200907 55

The 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine derivative BIM-46174 and its dimeric form BIM-46187 (1) are heterocyclized dipeptides that belong to the very few cell-permeable compounds known to preferentially silence Gαq proteins. To explore the chemical space of Gαq inhibitors of the BIM chemotype, a combinatorial approach was conducted towards a library of BIM molecules. This library was evaluated in a second messenger-based fluorescence assay to analyze the activity of Gα ...[more]

PMID: 32428383

Similar Datasets

Project description:The homomeric α7 nicotinic receptor (α7 nAChR) is widely expressed in the human brain that could be activated to suppress neuroinflammation, oxidative stress and neuropathic pain. Consequently, a number of α7 nAChR agonists have entered clinical trials as anti-Alzheimer's or anti-psychotic therapies. However, high-resolution crystal structure of the full-length α7 receptor is thus far unavailable. Since acetylcholine-binding protein (AChBP) from Lymnaea stagnalis is most closely related to the α-subunit of nAChRs, it has been used as a template for the N-terminal domain of α-subunit of nAChR to study the molecular recognition process of nAChR-ligand interactions, and to identify ligands with potential nAChR-like activities.Here we report the discovery and optimization of novel acetylcholine-binding protein ligands through screening, structure-activity relationships and structure-based design. We manually screened in-house CNS-biased compound library in vitro and identified compound 1, a piperidine derivative, as an initial hit with moderate binding affinity against AChBP (17.2% inhibition at 100 nmol/L). During the 1st round of optimization, with compound 2 (21.5% inhibition at 100 nmol/L) as the starting point, 13 piperidine derivatives with different aryl substitutions were synthesized and assayed in vitro. No apparent correlation was demonstrated between the binding affinities and the steric or electrostatic effects of aryl substitutions for most compounds, but compound 14 showed a higher affinity (Ki=105.6 nmol/L) than nicotine (Ki=777 nmol/L). During the 2nd round of optimization, we performed molecular modeling of the putative complex of compound 14 with AChBP, and compared it with the epibatidine-AChBP complex. The results suggested that a different piperidinyl substitution might confer a better fit for epibatidine as the reference compound. Thus, compound 15 was designed and identified as a highly affinitive acetylcholine-binding protein ligand. In this study, through two rounds of optimization, compound 15 (Ki=2.8 nmol/L) has been identified as a novel, piperidine-based acetylcholine-binding protein ligand with a high affinity.

Dataset Information

Tetrahydroimidazo[1,2-a]pyrazine Derivatives: Synthesis and Evaluation as G?q -Protein Ligands.

Publications

Tetrahydroimidazo[1,2-a]pyrazine Derivatives: Synthesis and Evaluation as Gα<sub>q</sub> -Protein Ligands.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets