title: Synthesis and structure-activity relationships of 1-aralkyl-4-benzylpiperidine and 1-aralkyl-4-benzylpiperazine derivatives as potent sigma ligands.
abstract: In the attempt to define more accurately structure-affinity relationships for sigma(1) and sigma(2) ligands, we synthesized and tested on sigma subtype receptors a series of aralkyl derivatives of 4-benzylpiperidine, in which the effect of modifications on the aralkyl moiety was studied in a systematic way. The affinity of the compounds here described varied to a great extent, with a sigma(2)/sigma(1) selectivity ranging from 0.1 to 9. Thus, to confirm the ability of the piperazine derivative to bind to sigma(1) receptors in a different way than piperidines, we synthesized and tested a series of piperazine compounds; the comparison of their affinity with that of the corresponding piperidines strongly supports the possibility of a different binding mode. While the compounds here described are on the whole selective for sigma vs serotonin 5-HT(1A) and dopamine D(2) receptors, 9aa, 9ba and 9ab possess a remarkable affinity for both sigma and 5-HT(1A) receptors, with K(i) in the nanomolar range, and are selective with respect to D(2) receptors. They displayed also a partial agonist profile in a human 5-HT(1A) [(35)S]GTP gamma S binding assay, suggesting their potential use as atypical antipsychotic agents.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Universitá di Modena and Reggio Emilia, Via Campi 183, 41100 Modena, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Costantino
authors.forename: Francesca
authors.initials: F
authors.lastname: Gandolfi
authors.forename: Claudia
authors.initials: C
authors.lastname: Sorbi
authors.forename: Silvia
authors.initials: S
authors.lastname: Franchini
authors.forename: Orazio
authors.initials: O
authors.lastname: Prezzavento
authors.forename: Franco
authors.initials: F
authors.lastname: Vittorio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ronsisvalle
authors.forename: Amedeo
authors.initials: A
authors.lastname: Leonardi
authors.forename: Elena
authors.initials: E
authors.lastname: Poggesi
authors.forename: Livio
authors.initials: L
authors.lastname: Brasili
mesh_terms: D000818:Animals; D001665:Binding Sites; D001671:Biochemistry / Q000379:methods; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011957:Receptors, Opioid / Q000819:agonists / Q000187:drug effects / Q000235:genetics; D017480:Receptors, sigma / Q000819:agonists* / Q000187:drug effects / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
chemical_list: D008024:Ligands; D010879:Piperazines; D010880:Piperidines; D044282:Receptor, Serotonin, 5-HT1A; D017448:Receptors, Dopamine D2; D011957:Receptors, Opioid; D017480:Receptors, sigma; D058825:Serotonin 5-HT1 Receptor Agonists; D000097605:Sigma-1 Receptor