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Abstract
Based on the pharmacophore model of Glennon the conformationally restricted σ1 receptor ligand 2 with a 1,3‐dioxane moiety has been designed and synthesized. The three step synthesis (transacetalization with pentane‐1,3,5‐triol, tosylation, and nucleophilic substitution with benzylamine) provided diastereoselectively the cis‐configured 1,3‐dioxane 2 in good yields. The 1,3‐dioxane 2 represents a potent σ1 receptor ligand (Ki = 19 nM) with moderate selectivity over the σ2 subtype (Ki = 92 nM) and excellent selectivity against more than 60 other targets. Additionally the hERG K+ channel is not affected by 2. In the capsaicin assay 2 showed extraordinarily high analgesic activity with more than 70% analgesia at the very low dose of 0.25 mg/kg body weight, which indicates σ1 antagonistic activity. Since 2 does only interact with σ1 receptors, the in‐vivo antiallodynic activity of 2 must be attributed to the σ1 antagonistic activity.
A three step synthesis provided diastereoselectively the cis‐configured 1,3‐dioxane 2 in good yields. In the capsaicin assay this compound is extraordinarily potent indicating σ1 antagonistic activity. This novel class of antiallodynic σ1 antagonists will be further exploited for the development of novel drugs for the treatment of neuropathic pain.
| Authors: | Utech, Tina; Köhler, Jens; Buschmann, Helmut; Holenz, Jörg; Vela, Jose Miguel; Wünsch, Bernhard | |
| Journal: | Archiv der Pharmazie | |
| Year: | 2011 | |
| Pages: | n/a | |
| DOI: | 10.1002/ardp.201000365 | |
| Publication date: | 20-05-2011 |
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