HETEROCYCLIC AMINO-ALCOHOLS RELATED TO IFENPRODIL AS SIGMA-RECEPTOR LIGANDS - BINDING AND CONFORMATIONAL-ANALYSES

The interaction of a novel series of heterocyclic amino alcohols with the sigma 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 [H-3]R(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperi([H-3]3-PPP) to rat cerebral cortical membranes. All compounds recognised two populations of binding sites labelled by [H-3]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 alpha(1)-adrenoceptors labelled by [H-3]prazosin, where the pattern of inhibition appears to be stereospecific, unlike that seen with the binding of [H-3]3-PPP. The amino alcohols had negligible affinity for sites labelled by the N-methyl-D-aspartate channel ligand, [H-3]-(N-1-[thienyl]cyclohexyl)piperidine. Quantitative conformational analyses indicated that the heterocyclic amino alcohols and ifenprodil fitted well to a sigma receptor site model; low energy conformers could be superimposed like other potent sigma receptor ligands with confidence to the sigma receptor model. Our results define a new class of sigma receptor ligands and extend the understanding of the molecular requirements for drugs active at the sigma receptor.