A comparison of (−)-deoxybenzomorphans devoid of opiate activity with their dextrorotatory phenolic counterparts suggests role of σ2 receptors in motor function

Abstract Three novel benzomorphans, (+)-N-benzylnormetazocine, (−)-deoxy-N-benzylnormetazocine, and (−)-deoxypentazocine were tested for their ability to produce circling behavior in rats following intranigral microinjections. Dose studies revealed the following rank order of potency: (−)-deoxypentazocine > (−)-deoxy-N-benzylnormetazocine > (+)-N-benzylnormetazocine. This rank order approximates that for affinities for σ 2 receptors but not σ 1 receptors. It is very unlikely that the effects of the (−)-deoxybenzomorphans were mediated by opiate receptors for the following reasons: (1) consistent with the known requirement for the phenolic hydroxyl group for opiate activity, both (−)-deoxy compounds showed very low affinity for opiate receptors; (2) naloxone (4 μg) co-administered with (−)-deoxy-N-benzylnormetazocine failed to reduce its efficacy; (3) both (−)-deoxy compounds failed to produce marked analgesic effects in the tail flick test following systemic injections of 20 mg/kg s.c. These findings suggest that σ 2 receptors mediated the motor effects of σ ligands in rats.