title: Synthesis of (+)- and (-)-cis-2-[(1-adamantylamino)-methyl]-1-phenylcyclopropane derivatives as high affinity probes for sigma1 and sigma2 binding sites.
abstract: Selective ligands for either sigma1 (sigma1) or sigma2 binding sites are potentially useful for gaining a better understanding of the physiological functions of these proteins. Moreover, potent and selective homochiral sigma1 and sigma2 binding site ligands represent leads to potential radioligands for tumour imaging with positron emission tomography (PET). On the basis of their structural similarity to previous leads, new (+)- and (-)-cis-2-[(1-adamantylamino)-methyl]-1-phenylcyclopropane derivatives were synthesised and their binding affinities for sigma1 and sigma2 binding sites were determined. Each enantiomer showed high affinity for both sigma1 and sigma2 binding sites, but only (-)-cis-methyl-2-[[1-adamantyl(methyl)amino]methyl]-1-phenylcyclopropane-carboxylate, (-)-4, showed appreciable selectivity for binding to sigma1 versus sigma2 sites. The enantiomers of cis-(2-[[1-adamantyl(methyl)amino]methyl]-1-phenylcyclopropyl)methanol, 6, expressed the highest affinity for sigma1 and sigma2 binding sites. Ligands (-)-4, (+)-6 and (-)-6 might be rapidly labelled in their N-methyl groups by methylation of the N-desmethyl analogues with [11C]iodomethane to provide prospective radioligands for PET. The N-desmethyl analogues, which are also high affinity ligands, were prepared and shown to undergo satisfactory methylation with iodomethane.
authors.affiliation: Department of Pharmaceutical Sciences, University of Catania, Catana, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Marrazzo
authors.forename: Orazio
authors.initials: O
authors.lastname: Prezzavento
authors.forename: Maria S
authors.initials: MS
authors.lastname: Pappalardo
authors.forename: Ennio
authors.initials: E
authors.lastname: Bousquet
authors.forename: Manuela
authors.initials: M
authors.lastname: Iadanza
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ronsisvalle
mesh_terms: D001665:Binding Sites; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D017480:Receptors, sigma / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D003521:Cyclopropanes; D017480:Receptors, sigma