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

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.