Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 230, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114113
Keywords
sigma(1) receptors; Conformational restriction; Tropanes; Stereochemistry; Configuration; X-ray crystal structure analysis; Eudismic ratio; Subtype selectivity; Antiallodynic activity; Antagonistic activity
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Funding
- Research Training Group Chemical biology of ion channels - Deutsche Forschungsgemeinschaft (DFG) , Germany
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This study synthesized several high affinity sigma(1) ligands by replacing the piperidine ring and introducing a bicyclic tropane system. Two of these compounds showed high antiallodynic activity in vivo and exhibited high selectivity for the sigma(1) receptor.
Following the concept of conformational restriction to obtain high affinity sigma(1) ligands, the piperidine ring of eliprodil was replaced by the bicyclic tropane system and an exocyclic double bond was introduced. The envisaged benzylidenetropanes 9 were prepared by conversion of tropanone 10 into the racemic mixture of (Z)-14 and (E)-14. Reaction of racemate (Z)-14/(E)-14 with enantiomerically pure (R)-or (S)- configured 2-phenyloxirane provided mixtures of diastereomeric beta-aminoalcohols (R,Z)-9 and (R,E)-9 as well as (S,Z)-9 and (S,E)-9, which were separated by chiral HPLC, respectively. X-ray crystal structure analysis of (S,Z)-9 allowed the unequivocal assignment of the configuration of all four stereoisomers. In receptor binding studies with radioligands, (R,E)-9 and (S,Z)-9 showed subnanomolar sigma(1) affinity with eudismic ratios of 8.3 and 40. In both compounds the 4-fluorophenyl moiety is oriented towards (S)-configured C-5 of the tropane system. Both compounds display high selectivity for the sigma(1) receptor over the G2 subtype but moderate selectivity over GluN2B NMDA receptors. In vivo, (R,E)-9 (K-i(sigma(1))1/4 0.80 nM) showed high antiallodynic activity in the capsaicin assay. The effect of (R,E)-9 could be reversed by pre administration of the sigma(1) agonist PRE-084 confirming the sigma(1) antagonistic activity of (R,E)-9. (C) 2022 Elsevier Masson SAS. All rights reserved.
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