Exploring the importance of piperazine N-atoms for sigma-2 receptor affinity and activity in a series of analogs of 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28)

σ2-Agonist 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (7, PB 28), which proved to revert doxorubicin resistance in breast cancer cells,was taken as a template to prepare new analogs. One of the two basic N-atoms was alternatively replaced by amethine or converted into an amide or ammonium function, with the aim of finding out which of them was essential for σ2 receptor affinity and activity. Some simply 4-substituted 1-cyclohexylpiperazineswere also investigated.None of the compounds was as high-affinity as 7 (σ2Ki=0.68, σ1Ki=0.38 nM), proving that both basicN-atoms ensure better σ2 receptor binding. Amide 36 emerged as high-affinity (Ki=0.11 nM) and noteworthy selective (1627-fold) σ1 ligand. Small N-cyclohexylpiperazine 59 displayed the highest σ2 affinity (Ki = 4.70 nM). The σ2/σ1 selectivities were generally low. Antiproliferative assay in SK-N-SH cells revealed piperidines 24 and 15 as putative σ2 agonists (EC50s 1.40 and 3.64 μM respectively) more potent than 7.