title: 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.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Hittorfstraße 58-62, 48145 Münster, Germany.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Jasper
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Kirstin
authors.initials: K
authors.lastname: Lehmkuhl
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Vela
authors.forename: Helmut
authors.initials: H
authors.lastname: Buschmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Holenz
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D001554:Benzene / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D006801:Humans; D008024:Ligands; D008872:Microwaves; D009584:Nitrogen / Q000737:chemistry*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017480:Receptors, sigma / Q000378:metabolism*; D013141:Spiro Compounds / Q000737:chemistry*; D013379:Substrate Specificity
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D008024:Ligands; D011759:Pyrrolidines; D017480:Receptors, sigma; D013141:Spiro Compounds; D001554:Benzene; D009584:Nitrogen