Synthesis and binding affinities of methylvesamicol analogs for the acetylcholine transporter and sigma receptor

Abstract

We synthesized methylvesamicol analogs 13– 16 and investigated the binding characteristics of 2-[4-phenylpiperidino]cyclohexanol (vesamicol) and methylvesamicol analogs 13– 16, with a methyl group introduced into the 4-phenylpiperidine moiety, to sigma receptors (σ-1, σ-2) and to vesicular acetylcholine transporters (VAChT) in membranes of the rat brain and liver. In competitive inhibition studies, (−)- o-methylvesamicol [(−)-OMV] ( 13) ( K i = 6.7 nM), as well as (−)-vesamicol ( K i = 4.4 nM), had a high affinity for VAChT. (+)- p-Methylvesamicol [(+)-PMV] ( 16) ( K i = 3.0 nM), as well as SA4503 ( K i = 4.4 nM), reported as a σ-1 mapping agent for positron emission tomography (PET), had a high affinity for the σ-1 receptor. The binding affinity of (+)-PMV ( 16) for the σ-1 receptor ( K i = 3.0 nM) was about 13 times higher than that for the sigma-2 (σ-2) receptor ( K i = 40.7 nM). (+)-PMV ( 16) ( K i = 199 nM) had a much lower affinity for VAChT than SA4503 ( K i = 50.2 nM) and haloperidol ( K i = 41.4 nM). These results showed that the binding characteristics of (−)-OMV ( 13) to VAChT were similar to those of (−)-vesamicol and that (+)-PMV ( 16) bound to the σ-1 receptor with high affinity. In conclusion, (−)-OMV ( 13) and (+)-PMV ( 16), which had a suitable structure, with a methyl group for labeling with 11C, may become not only a new VAChT ligand and a new type of σ receptor ligand, respectively, but may also become a new target compound of VAChT and the σ-1 receptor radioligand for PET, respectively.