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 (sigma) receptor ligands modulates off-target activity and subtype selectivity.

Article Details

Citation

Copy to clipboard

Banister SD, Moussa IA, Jorgensen WT, Chua SW, Kassiou M

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 (sigma) receptor ligands modulates off-target activity and subtype selectivity.

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3622-6. doi: 10.1016/j.bmcl.2011.04.098. Epub 2011 Apr 28.

PubMed ID

21555222 [ View in PubMed

]

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 (sigma) receptor ligands were synthesized and evaluated for their affinity against sigma receptors and dopamine receptors. The hybrid trishomocubane-derived ligands (4-6) showed good selectivity for sigma(1) and sigma(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, sigma(1)K(i)=27 nM, sigma(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 sigma(1) affinity in the series, benzamide 4 (sigma(1)K(i)=7.6 nM, sigma(2)K(i)=225 nM) showed a complete reversal of the subtype selectivity displayed by the highly sigma(2) selective parent benzamide, RHM-2 (3, sigma(1)K(i)=10412 nM, sigma(2)K(i)=13.3 nM).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Haloperidol	Dopamine D1 receptor	Ki (nM)	25	N/A	N/A	Details
Haloperidol	Dopamine D2 receptor	Ki (nM)	1	N/A	N/A	Details
Haloperidol	Dopamine D3 receptor	Ki (nM)	29	N/A	N/A	Details