Exploring the Importance of Piperazine N-Atoms for σ2 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)

sigma(2)-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 wits alternatively replaced by it methine or converted into an amide or ammonium function, with the aim of finding out which of them was essential For sigma(2) receptor affinity and activity. Some simply 4-substituted 1-cyclohexylpiperazines were also investigated. None of the compounds was as high-affinity as 7 (sigma K-2(i) = 0.68, sigma K-1(i) = 0.38 nM), proving that both basic N-atoms ensure better sigma(2) receptor binding. Amide 36 emerged as high-affinity (K-i = 0.11 nM) and noteworthy selective (1627-fold) or, ligand. Small N-cyclohexylpiperazine 59 displayed the highest sigma(2) affinity (K-i = 4.70 nM). The sigma(2)/sigma(1) selectivities were generally low. Antiproliferative assay in SK-N-SH cells revealed piperidines 24 and 15 as putative sigma(2), agonists (EC(50)s 1.40 and 3.64 mu M respectively) more potent than 7.