Microwave assisted synthesis of spirocyclic pyrrolidines – σ1 receptor ligands with modified benzene-N-distance

Two series of σ1 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 σ1 affinity of the spirocyclic ligands correlates nicely with the benzene-N-distance, i.e. 2 < 3 < 4 < 1. The σ1 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 σ1 ligand (Ki = 25 nM) due to its high selectivity against the σ2 subtype (>40-fold), the NMDA receptor and 5-HT6 and 5-HT7 receptors. Moreover, 4a did not inhibit the hERG channel in the heart.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Spirocyclic pyrrolidines were synthesized. ► Spiro[[2]benzofuran-1,3′-pyrroldines] represent potent σ1 ligands. ► A correlation between the benzene-N-distance and the σ1 affinity was found. ► The most potent σ1 ligands show high selectivity against related systems. ► The hERG-potassium channel of the heart is not touched by the ligands.