Thiophene bioisosteres of spirocyclic sigma receptor ligands. 1. N-substituted spiro[piperidine-4,4'-thieno[3,2-c]pyrans].
Herein, the synthesis and pharmacological evaluation of thiophene bioisosteres of the highly potent spirocyclic benzopyran 1 are detailed. The synthesis of 1-benzyl-6'-methoxy-6',7'-dihydrospiro[piperidine-4,4'-thieno[3.2- c]pyran] (2a) was performed starting with 3-bromothiophene (3). After introduction of the acetaldehyde substructure (7), halogen metal exchange, addition of 1-benzylpiperidin-4-one, and cyclization led to the spirocyclic thienopyran 2a. The removal of the benzyl group afforded the secondary amine 2f, which was substituted with various residues. With respect to sigma 1 affinity the N-benzyl derivative 2a, the N-cyclohexylmethyl derivative 2d, and the N-p-fluorobenzyl derivative 2i represent the most potent compounds of this series binding with K i values of 0.32, 0.29, and 0.62 nM, respectively. Electronic properties of the substituents have only little impact on sigma 1 affinity. The most potent sigma 1 ligands display high selectivity against sigma 2, 5-HT 1A, 5-HT 6, 5-HT 7, alpha 1A, alpha 2, and NMDA receptors. The activity of 2a in the mouse capsaicin assay seems to indicate sigma 1 antagonistic activity.
Oberdorf
Christoph
C
Institut für Pharmazeutische and Medizinische Chemie der Universität Müünster, Hittorfstrasse 58-62, D-48149 Münster, Germany.
Schepmann
Dirk
D
Vela
Jose Miguel
JM
Diaz
Jose Luis
JL
Holenz
Jörg
J
Wünsch
Bernhard
B
D000478:Alkylation; D000818:Animals; D003500:Cyclization; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry*; D011485:Protein Binding; D011714:Pyrans / Q000737:chemistry* / Q000627:therapeutic use; D051381:Rats; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D013141:Spiro Compounds / Q000737:chemistry* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry*
D008024:Ligands; D010880:Piperidines; D011714:Pyrans; D017480:Receptors, sigma; D013141:Spiro Compounds; D013876:Thiophenes; C032727:piperidine