Exploiting the power of stereochemistry in drug action: 3-[(2S,6S,11S)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide as potent sigma 1 receptor antagonist.

(+)-(2S,6S,11S)- and (-)-(2R,6R,11R)-benzomorphan derivatives have a different binding affinity for sigma-1 (σ1R) and opioid receptor, respectively. In this study we describe the synthesis of the (+)-enantiomer [(+)-LP1] of the benzomorphan MOR-agonist/DOR-antagonist LP1 [(-)-LP1]. The binding affinity of both (+)-LP1 and (-)-LP1 for σ1R and sigma-2 recep-tor (σ2R) was tested. Moreover, (+)-LP1 opioid receptor binding affinity was also investigated. Finally, (+)-LP1 was tested in a mouse model of inflammatory pain. Our results showed a nanomolar σ1R and binding affinity for (+)-LP1. Both (+)-LP1 and (-)-LP1 elicited a significant analgesic effect in formalin test. Differently from (-)-LP1, the analgesic effect of (+)-LP1 was not reversed by naloxone suggesting a σ1R antagonist profile. Furthermore, σ1R agonist PRE-084 was able to unmask the σ1R antagonistic component of the benzomorphan compound. (+)-LP1 could constitute a useful lead compound to develop new analgesics based on mechanisms of action alternative to opioid receptors activation.(+)-LP1 could constitute an useful lead compound to develop new analgesics based on mechanisms of action alternative to opioid receptors activation.