Abstract
A series of 1-phenyl-3-azabicyclo(3.1.0)hexanes were synthesized as more conformationally restricted prototypical σ ligands 3-phenylpiperidines with the aim to developing new σ ligands. Compared with 3-phenylpiperidines reported by Largent et al., binding data showed that conformational restriction was not detrimental for σ receptor affinity. Specifically, except for secondary amine 4, all racemic 1-phenyl-3-azabicyclo(3.1.0)hexane derivatives (12-19) showed moderate to high affinity for both σ1 and σ2 receptors. Dextrorotatory isomers with the same configuration of 3-phenylpiperidines to C-1 carbon linked to the phenyl ring showed a better affinity and selectivity for σ1 receptors compared to the respective levorotatory isomers. Compounds (+)-14 and (+)-15 displayed very high affinity for σ1 (Ki = 0.9 and 2.3 nM respectively) but low selectivity for receptor subtypes. Compound (+)-18 with N-phenethyl substituent embodies the highest selectivity for σ1 receptors.
Highlights
Compared with 3-phenylpiperidines reported by Largent et al, binding data showed that conformational restriction was not detrimental for σ receptor affinity
Dextrorotatory isomers with the same configuration of 3-phenylpiperidines to C-1 carbon linked to the phenyl ring showed a better affinity and selectivity for σ1 receptors compared to the respective levorotatory isomers
Sigma (σ) receptors are typical binding sites interacting with several psychoactive drugs including haloperidol, benzomorphans and phencyclidine
Summary
Sigma (σ) receptors are typical binding sites interacting with several psychoactive drugs including haloperidol, benzomorphans and phencyclidine.1-5 The σ1 subtype exhibits high affinity for (+)-benzomorphans such as (+)-pentazocine and (+)-N-allylnormetazocine (SKF10,047) and a reduced affinity for the respective (–)-enantiomers.Based on animal model studies, this subtype seems to be involved in cocaine induced behavioral changes, in opiate induced analgesia, steroid-induced mental disturbances and alterations in immune functions.6-8The σ2 subtype showed low affinity for (+)-pentazocine and (+)-SKF-10,047 and (–)-isomers did not differentiate between the two sites.Several pharmacological studies showed that σ2 receptors are expressed in high concentration in tumor cell lines and that they are involved in proliferation and cell viability.9 selective σ1 and σ2 ligands with agonist or antagonist properties might be potential drugs for clinical treatment of memory and learning disorders, psychoses, cocaine abuse, dyskinesia induced by classical antipsychotic therapy and cancer. Compared with 3-phenylpiperidines reported by Largent et al, binding data showed that conformational restriction was not detrimental for σ receptor affinity. Except for secondary amine 4, all racemic 1-phenyl-3-azabicyclo[3.1.0]hexane derivatives [12,13,14,15,16,17,18,19] showed moderate to high affinity for both σ1 and σ2 receptors.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
