Trishomocubanes: novel sigma-receptor ligands modulate amphetamine-stimulated [3H]dopamine release.

Several trishomocubane analogues of the type 4-azahexacyclo [5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecane exhibited moderate to high affinity at sigma-receptor subtypes and low or negligible affinity at dopamine and serotonin transporters (SERT). Selected compounds were examined for their effects on amphetamine-stimulated [3H]dopamine release from striatal slices in vitro. Compounds 1, 2, 3 and 4 significantly enhanced amphetamine-stimulated release in a concentration-dependent manner. Compound 4, with the highest affinity and selectivity for the sigma(2)-receptor subtype, displayed the greatest potency. The enhancement produced by 1 and 2 was fully reversed by the selective sigma(2) antagonists 1'-[4-[1-(4-fluorophenyl)-1-H-indol-3-yl]-1-butyl]spiro[iso-benzofuran-1(3H), 4'piperidine] (Lu28-179), endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-(1-methyl)ethyl-2-oxo-1-H-benzimidazole-1-carboxyamidehydrochloride (BIMU-8) and the non-subtype selective antagonist N-[2-(3,4-dichlorophenyl)-ethyl]-N-methyl-2-pyrrolidinyl)ethylamine (BD1008). These data suggested a potential role for compounds 1 through 4 as sigma(2)-receptor agonists in functional studies. In addition, a D(3)-trishomocubane compound 5 displayed low affinity at sigma receptors (K(i)=3 microM) and moderate affinity at dopamine transporters (K(i)=623 nM). Compound 5 significantly inhibited the potentiation mediated by compound 2, presumably through sigma(2)-receptor antagonism, or a direct action on dopamine transporters.