Synthesis of tropane-based σ1 receptor antagonists with antiallodynic activity

Following the concept of conformational restriction to obtain high affinity σ1 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 σ1 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 σ1 receptor over the σ2 subtype but moderate selectivity over GluN2B NMDA receptors. In vivo, (R,E)-9 (Ki(σ1) = 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 σ1 agonist PRE-084 confirming the σ1 antagonistic activity of (R,E)-9.