Improving selectivity preserving affinity: New piperidine-4-carboxamide derivatives as effective sigma-1-ligands

• New sigma-1 receptor ligands were designed and synthesized.
• All derivatives showed high affinity and high selectivity for the target receptor.
• In silico affinity predictions were confirmed by experimental data.
• Compounds featuring a quinoline moiety displayed the best biological profile.
• No compound exhibited affinity for the NMDA receptor.

We report the design, synthesis and binding evaluation against σ1 and σ2 receptors of a series of new piperidine-4-carboxamide derivatives variously substituted on the amide nitrogen atom. Specifically, we assessed the effects exerted on σ receptor affinity by substituting the N-benzylcarboxamide group present on a series of compounds previously synthesized in our laboratory with different cyclic or linear moieties. The synthesized compounds 2a–o were tested to estimate their affinity and selectivity toward σ1 and σ2 receptors. Very high σ1 affinity (Ki = 3.7 nM) and Kiσ2/Kiσ1 selectivity ratio (351) were found for the tetrahydroquinoline derivative 2k, featuring a 4-chlorobenzyl moiety linked to the piperidine nitrogen atom.

New piperidine-4-carboxamide derivatives were synthesized and an evaluation of their affinity towards σ and NMDA receptors was performed by radioligand binding assays. These derivatives showed an interesting affinity towards σ1 receptors and a very high selectivity profile against the other receptor systems.Figure optionsDownload as PowerPoint slide