title: Molecular hybridization of 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecane-3-ol with sigma (σ) receptor ligands modulates off-target activity and subtype selectivity.
abstract: A series of N-substituted 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ols incorporating the respective arylalkyl subunits from several known sigma (σ) receptor ligands were synthesized and evaluated for their affinity against σ receptors and dopamine receptors. The hybrid trishomocubane-derived ligands (4-6) showed good selectivity for σ(1) and σ(2) receptors over multiple dopamine receptors. The molecular hybrid obtained from haloperidol and 4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ol (4, σ(1)K(i)=27 nM, σ(2)K(i)=55 nM) showed reduced affinity for D(1)-D(5) dopamine receptors when compared to haloperidol itself. The compound with the greatest σ(1) affinity in the series, benzamide 4 (σ(1)K(i)=7.6 nM, σ(2)K(i)=225 nM) showed a complete reversal of the subtype selectivity displayed by the highly σ(2) selective parent benzamide, RHM-2 (3, σ(1)K(i)=10412 nM, σ(2)K(i)=13.3 nM).
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Banister
authors.forename: Iman A
authors.initials: IA
authors.lastname: Moussa
authors.forename: William T
authors.initials: WT
authors.lastname: Jorgensen
authors.forename: Sook Wern
authors.initials: SW
authors.lastname: Chua
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
mesh_terms: D000473:Alkanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003500:Cyclization; D007851:Dodecanol / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006220:Haloperidol / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D015394:Molecular Structure; D011954:Receptors, Dopamine / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism*; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D000473:Alkanes; D001372:Aza Compounds; D008024:Ligands; D011954:Receptors, Dopamine; D017480:Receptors, sigma; C007548:n-dodecane; D007851:Dodecanol; D006220:Haloperidol