title: One-pot synthesis and sigma receptor binding studies of novel spirocyclic-2,6-diketopiperazine derivatives.
abstract: New spirocyclic-2,6-diketopiperazine derivatives containing benzylpiperidine and cycloalkane moieties were synthesized by a one-pot two-step sequential Ugi/intramolecular N-amidation process in moderate to good yields. The in vitro ligand-binding profile studies performed on the sigma-1 and sigma-2 receptors revealed that the σ1 affinities and subtype selectivities of three spirocyclic piperidine derivatives are generally comparable to those of spirocycloalkane analogues. Compared to the low σ1 affinities obtained for cycloalkyl-substituted spirocyclic-2,6-diketopiperazines with n=2, those with n=1 proved to have optimal fitting with σ2 subtype by exhibiting higher affinities. Moreover, the best binding affinity and subtype selectivity was identified for compound 3c with Kiσ1=5.9±0.5nM and Kiσ2=563±21nM as well as 95-fold σ1/σ2 selectivity ratio, respectively.
authors.affiliation: School of Chemistry, College of Science, University of Tehran, PO Box 14155 6455, Tehran, Iran. Electronic address: ghandi@khayam.ut.ac.ir.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Ghandi
authors.affiliation: School of Chemistry, College of Science, University of Tehran, PO Box 14155 6455, Tehran, Iran.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Sherafat
authors.affiliation: Radiation Application Research School, Nuclear Science and Technology Research Institute (NSTRI), PO Box 11365-3486, Tehran, Iran.
authors.forename: Masoud
authors.initials: M
authors.lastname: Sadeghzadeh
authors.affiliation: Radiation Application Research School, Nuclear Science and Technology Research Institute (NSTRI), PO Box 11365-3486, Tehran, Iran.
authors.forename: Behrouz
authors.initials: B
authors.lastname: Alirezapour
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D054659:Diketopiperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
chemical_list: D054659:Diketopiperazines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C106107:sigma-2 receptor
keywords: Sigma receptor ligand; Spirocyclic piperidines; Spirocyclic-2,6-diketopiperazines; Ugi reaction