Synthesis and binding assays of novel 3,3-dimethylpiperidine derivatives with various lipophilicities as σ1 receptor ligands

Starting from two carbocyclic analogs, a series of 3,3-dimethylpiperidine derivatives was prepared and tested in radioligand binding assays at σ1 and σ2 receptors, and at Δ8-Δ7 sterol isomerase (SI) site. The novel compounds mostly bear heterocyclic rings or bicyclic nucleus of differing lipophilicities. Compounds 18a and 19a,b demonstrated the highest σ1 affinity (Ki = 0.14-0.38 nM) with a good selectivity versus σ2 binding. Among them, 18a had the lowest C log D value (3.01) and only 19b was selective versus SI too. Generally, it was observed that more planar and hydrophilic heteronuclei conferred a decrease in affinity for both σ receptor subtypes.