Szczepanska, Katarzyna and Podlewska, Sabina and Dichiara, Maria and Gentile, Davide and Patamia, Vincenzo and Rosier, Niklas and Moennich, Denise and Ruiz Cantero, Ma Carmen and Karcz, Tadeusz and Lazewska, Dorota and Siwek, Agata and Pockes, Steffen and Cobos, Enrique J. and Marrazzo, Agostino and Stark, Holger and Rescifina, Antonio and Bojarski, Andrzej J. and Amata, Emanuele and Kiec-Kononowicz, Katarzyna (2022) Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H-3 and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties. ACS CHEMICAL NEUROSCIENCE, 13 (1). pp. 1-15. ISSN 1948-7193,
Full text not available from this repository. (Request a copy)Abstract
In an attempt to extend recent studies showing that some clinically evaluated histamine H-3 receptor (H3R) antagonists possess nanomolar affinity at sigma-1 receptors (sigma R-1), we selected 20 representative structures among our previously reported H3R ligands to investigate their affinity at sigma Rs. Most of the tested compounds interact with both sigma receptors to different degrees. However, only six of them showed higher affinity toward sigma R-1 than sigma R-2 with the highest binding preference to sigma R-1 for compounds 5, 11, and 12. Moreover, all these ligands share a common structural feature: the piperidine moiety as the fundamental part of the molecule. It is most likely a critical structural element for dual H-3/sigma(1) receptor activity as can be seen by comparing the data for compounds 4 and 5 (hH(3)R = 3.17 and 7.70 nM, sigma R-1 K = 1531 and 3.64 nM, respectively), where piperidine is replaced by piperazine. We identified the putative protein-ligand interactions responsible for their high affinity using molecular modeling techniques and selected compounds 5 and 11 as lead structures for further evaluation. Interestingly, both ligands turned out to be high-affinity histamine H-3 and sigma(1) receptor antagonists with negligible affinity at the other histamine receptor subtypes and promising antinociceptive activity in vivo. Considering that many literature data clearly indicate high preclinical efficacy of individual selective sigma(l) or H3R ligands in various pain models, our research might be a breakthrough in the search for novel, dual-acting compounds that can improve existing pain therapies. Determining whether such ligands are more effective than single-selective drugs will be the subject of our future studies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | DIRECTED LIGANDS; INHIBITION; TARGET; POTENT; IDENTIFICATION; OPTIMIZATION; THERAPEUTICS; INVOLVEMENT; AGONISTS; BINDING; histamine H-3 receptor; sigma-1 receptor; sigma-2 receptor; piperazine derivatives; piperidine derivatives; dual targeting compounds; molecular docking; dynamics; functional characterization |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 21 Sep 2022 13:21 |
| Last Modified: | 21 Sep 2022 13:21 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47880 |
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