Referenced in: none

Automatically associated channels: Kv11.1

Title: Microwave assisted synthesis of spirocyclic pyrrolidines -σ1 receptor ligands with modified benzene-N-distance.

Authors: Annemarie Jasper, Dirk Schepmann, Kirstin Lehmkuhl, Jose Miguel Vela, Helmut Buschmann, Jörg Holenz, Bernhard Wünsch

Journal, date & volume: Eur J Med Chem, 2012 Jul , 53, 327-36

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22578786

Abstract
Two series of σ(1) ligands with a spiro[[2]benzopyran-1,3'-pyrrolidine] (3) and a spiro[[2]benzofuran-1,3'-pyrrolidine] (4) framework were synthesized and pharmacologically evaluated. Several reaction steps were considerably improved by microwave irradiation. The σ(1) affinity of the spirocyclic ligands correlates nicely with the benzene-N-distance, i.e. 2 < 3 < 4 < 1. The σ(1) affinity of both compound classes could be increased with large N-substituents (e.g. 2-phenylethyl, octyl). Nevertheless the benzyl derivative 4a represents the most promising σ(1) ligand (K(i) = 25 nM) due to its high selectivity against the σ(2) subtype (>40-fold), the NMDA receptor and 5-HT(6) and 5-HT(7) receptors. Moreover, 4a did not inhibit the hERG channel in the heart.