DEVELOPMENT OF PHENOXYALKYLPIPERIDINES AS HIGH-AFFINITY SIGMA-1 (s1) RECEPTOR LIGANDS WITH POTENT ANTI-AMNESIC ACTIVITY

The sigma-1 (σ1) receptor plays a significant role in many physiological functions and pathological disease states, and, as such, it represents an attractive therapeutic target for both agonists and antagonists. Here, we describe a novel series of phenoxyalkylpiperidines (Figure 1) that were prepared and tested at σ1, σ2, and sterol Δ8- Δ7 isomerase (SI) sites by in vitro radioligand binding assays. These new compounds are derivatives of the σ ligand 1-[3-(4-chlorophenoxy)propyl]-4-methylpiperidine (L1), which has been claimed as a therapeutic agent for CNS disorders and neuropathies. In order to explore the structure-affinity relationships (SAFIRs) of this class of compounds, we modified the aryloxyl and piperidine moieties and the linker that connects them. In particular, we evaluated the influence of the stereochemistry on σ receptors affinity and selectivity through the introduction of methyl groups either on the chain or on the piperidine ring. The affinity at σ1 and σ2 receptors and at Δ8-Δ7 sterol isomerase (SI) ranged from subnanomolar to micromolar Ki values. While the highest affinity was displayed at the σ1 receptor (Ki = 0.34 nM), the chirality introduced by a methyl substitution in the linker resulted only in slight differences. The higher was the degree of methylation on the piperidine ring the lower was the ligand affinity, in agreement with other classes of σ1 receptor ligands. Nevertheless, the shorter oxyethylenic chain was beneficial for the σ1 selectivity. Importantly, these shorter-chain compounds displayed potent antiamnesic effects associated with σ1 receptor agonism, in two different memory tests. Overall, phenoxyalkylpiperidines hold potential for the development of high affinity σ1 receptor agonists.