Title

Trishomocubanes: Novel σ-receptor ligands modulate amphetamine-stimulated [ 3H]dopamine release

Document Type

Journal Article

Publication Date

6-22-2001

Journal

European Journal of Pharmacology

Volume

422

Issue

1-3

DOI

10.1016/S0014-2999(01)01071-8

Keywords

σ Receptor; Amphetamine; Azahexacyclo[5.4.1.0 .0 .0 .0 ] dodecane 2,6 3,10 5,9 8,11; Dopamine release; Trishomocubane

Abstract

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 σ-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 σ 2-receptor subtype, displayed the greatest potency. The enhancement produced by 1 and 2 was fully reversed by the selective σ 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 (BD 1008). These data suggested a potential role for compounds 1 through 4 as σ 2-receptor agonists in functional studies. In addition, a D 3-trishomocubane compound 5 displayed low affinity at σ receptors (K i = 3 μM) and moderate affinity at dopamine transporters (K i = 623 nM). Compound 5 significantly inhibited the potentiation mediated by compound 2, presumably through σ 2-receptor antagonism, or a direct action on dopamine transporters. © 2001 Elsevier Science B.V.

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