Synthesis of tropane-based σ1 receptor antagonists with antiallodynic activity

European Journal of Medicinal Chemistry
2022.0

Abstract

Following the concept of conformational restriction to obtain high affinity σ<sub>1</sub> 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 β-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 σ<sub>1</sub> 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 σ<sub>1</sub> receptor over the σ<sub>2</sub> subtype but moderate selectivity over GluN2B NMDA receptors. In vivo, (R,E)-9 (K<sub>i</sub>(σ<sub>1</sub>) = 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 σ<sub>1</sub> agonist PRE-084 confirming the σ<sub>1</sub> antagonistic activity of (R,E)-9.

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