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Synthesis 2011(24): 3965-3974  
DOI: 10.1055/s-0031-1289607
FEATUREARTICLE
© Georg Thieme Verlag Stuttgart ˙ New York

Novel σ1 Receptor Ligands by Oxa-Pictet-Spengler Reaction of Pyrazolylethanol

Torsten Schläger, Dirk Schepmann, Bernhard Wünsch*
Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Hittorfstraße 58-62, 48149 Münster, Germany
Fax: +49(251)8332144; e-Mail: wuensch@uni-muenster.de;
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Publication History

Received 30 August 2011
Publication Date:
15 November 2011 (online)

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Abstract

The oxa-Pictet-Spengler reaction of 2-(1-phenylpyrazol-5-yl)ethanol required the weak acid pyridinium p-toluenesulfonate to provide pyrano[4,3-c]pyrazoles with additional functional groups in the side chain. These functional groups allow the introduction of various amino substituents into the side chain in position 4. In receptor binding studies the aminoethyl-substituted pyranopyrazoles revealed higher σ1 receptor affinities and σ1/σ2 selectivities than the shorter aminomethyl homologues. The pyranopyrazole bearing the phenylpiperidine substituent (K i = 0.99 nM) represents the most potent and that bearing the piperidine substituent the most selective (σ1/σ2 = 180) σ1 ligands of this series of compounds.

Keywords

σ1 receptor ligands - oxa-Pictet-Spengler reaction - annulated pyrazoles - pyrazolylethanol - structure affinity relationships

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