Molecular hybridization of 4-azahexacyclo[5.4.1.02,6.03,10.05,9.08,11] dodecane-3-ol with sigma (σ) receptor ligands modulates off-target activity and subtype selectivity

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). (C) 2011 Elsevier Ltd. All rights reserved.