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J Med Chem. 2008 Oct 23;51(20):6531-7. doi: 10.1021/jm8007739. Epub 2008 Sep 25.

Thiophene bioisosteres of spirocyclic sigma receptor ligands. 1. N-substituted spiro[piperidine-4,4'-thieno[3,2-c]pyrans].

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1
Institut für Pharmazeutische and Medizinische Chemie der Universität Müünster, Hittorfstrasse 58-62, D-48149 Münster, Germany.

Abstract

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.

PMID:
18816044
DOI:
10.1021/jm8007739
[Indexed for MEDLINE]

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