Karcz, Tadeusz and Szczepanska, Katarzyna and Mogilski, Szczepan and Moroz, Aleksandra and Olejarz-Maciej, Agnieszka and Humphrys, Laura J. and Pockes, Steffen and Siwek, Agata and Dubiel, Krzysztof and Staszewski, Marek and Calmels, Thierry and Waczynski, Krzysztof and Kiec-Kononowicz, Katarzyna (2024) Guanidine Derivative ADS1017, a Potent Histamine H3 Receptor Antagonist with Promising Analgesic Activity and Satisfactory Safety Profile. ACS CHEMICAL NEUROSCIENCE, 15 (24). pp. 4441-4457. ISSN 1948-7193
Full text not available from this repository. (Request a copy)Abstract
In this study, we selected 12 guanidine derivatives from the previously described ligand library and determined their affinity at histamine H-3 and H-4 receptors (H3R and H4R, respectively). Moreover, we also checked their intrinsic activity toward H3R and muscarinic M-1, M-2, and M-4 receptors (M1R, M2R, and M4R, respectively). Since ADS1017 has been proved to be the most selective and highly potent H-3 antagonist in our series, we chose it as the lead structure for further biological evaluation. To extend the study of its in vivo efficacy, we proposed an alternative synthetic route that resulted in an increased yield. Interestingly, ADS1017 showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models. Finally, as a result of comprehensive analysis of its off-target activity and ADMETox parameters, we confirmed the moderate selectivity of ADS1017 and its promising drug-like properties.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ARTIFICIAL MEMBRANE; FORMALIN INJECTION; NEUROPATHIC PAIN; GLOBAL BURDEN; H3 RECEPTOR; MODELS; DESIGN; PIPERIDINE; INHIBITOR; AFFINITY; guanidines; histamine H-3 receptor; muscarinic receptors; multi-target directed ligand; pain; functional characterization; ADMETox properties |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Oct 2025 05:13 |
| Last Modified: | 22 Oct 2025 05:13 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65233 |
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