Heterocyclic amino alcohols related to ifenprodil as σ receptor ligands: binding and conformational analyses

Abstract

The interaction of a novel series of heterocyclic amino alcohols with the σ receptor site was assessed using radioligand binding and computerized molecular modelling. All heterocyclic amino alcohols, like the structurally related ifenprodil, fully inhibited the specific binding of [ 3H]R(+)-3-(3-hydroxyphenyl)- N-(1-propyl)piperidine ([ 3H]3-PPP) to rat cerebral cortical membranes. All compounds recognised two populations of binding sites labelled by [ 3H]3-PPP and the proportion of sites in the high affinity state was 60–80% of the total sites. Some of the heterocyclic amino alcohols also displayed similar affinity for α 1-adrenoceptors labelled by [ 3H]prazosin, where the pattern of inhibition appears to be stereospecific, unlike that seen with the binding of [ 3H]3-PPP. The amino alcohols had negligible affinity for sites labelled by the N- methyl- D-aspartate channel ligand, [ 3H]-( N-1-[thienyl]cyclohexyl)piperidine. Quantitative conformational analyses indicated that the heterocyclic amino alcohols and ifenprodil fitted well to a σ receptor site model; low energy conformers could be superimposed like other potent σ receptor ligands with confidence to the σ receptor model. Our results define a new class of σ receptor ligands and extend the understanding of the molecular requirements for drugs active at the σ receptor.