title: Novel 1-phenylpiperazine and 4-phenylpiperidine derivatives as high-affinity sigma ligands.
abstract: sigma receptors may represent an exciting new approach for the development of novel psychotherapeutic agents. Unfortunately, many of the commonly used sigma ligands lack selectivity (e.g., many bind at phencyclidine or dopamine receptors) or suffer from other serious drawbacks. Recently, we described a series of 2-phenylaminoethanes that bind at sigma receptors with high affinity and selectivity. Because there is evidence that 1-phenylpiperazines can structurally mimic the 2-phenylaminoethane moiety, we prepared a series of 1-phenylpiperazines and related analogues and incorporated structural features already shown to enhance the sigma binding of the 2-phenylaminoethanes. Several of these derivatives bind at sigma receptors with high affinity (Ki = 1-10 nM) and lack appreciable affinity for phencyclidine and dopamine receptors. In as much as certain of these agents structurally resemble the high-affinity, but nonselective, sigma ligand haloperidol, and because they bind with 10 times the affinity of haloperidol, we have apparently identified what appears to be the primary sigma pharmacophore of that agent.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0540.
authors.forename: R A
authors.initials: RA
authors.lastname: Glennon
authors.forename: M Y
authors.initials: MY
authors.lastname: Yousif
authors.forename: A M
authors.initials: AM
authors.lastname: Ismaiel
authors.forename: M B
authors.initials: MB
authors.lastname: el-Ashmawy
authors.forename: J L
authors.initials: JL
authors.lastname: Herndon
authors.forename: J B
authors.initials: JB
authors.lastname: Fischer
authors.forename: A C
authors.initials: AC
authors.lastname: Server
authors.forename: K J
authors.initials: KJ
authors.lastname: Howie
mesh_terms: D000818:Animals; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008024:Ligands; D010879:Piperazines / Q000138:chemical synthesis / Q000378:metabolism*; D010880:Piperidines / Q000138:chemical synthesis / Q000378:metabolism*; D011869:Radioligand Assay; D011954:Receptors, Dopamine / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism*; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D010879:Piperazines; D010880:Piperidines; D011954:Receptors, Dopamine; D017981:Receptors, Neurotransmitter; D011957:Receptors, Opioid; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; C048151:4-phenylpiperidine; C031503:phenylpiperazine