Synthesis and binding assays of novel 3,3-dimethylpiperidine derivatives with various lipophilicities as sigma-1 receptor ligands

Starting from two carbocyclic analogs, a series of 3,3-dimethylpiperidine derivatives was prepared and tested in radioligand binding assays at r1 and r2 receptors, and at D8–D7 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 r1 affinity (Ki = 0.14–0.38 nM) with a good selectivity versus r2 binding. Among them, 18a had the lowest ClogD 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 r receptor subtypes.