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).
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 was alternatively replaced by a 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(2)K(i) = 0.68, sigma(1)K(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) sigma(1) 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 muM respectively) more potent than 7.
Dipartimento Farmacochimico, Universita degli Studi di Bari, I-70125 Bari, Italy. berardi@farmchim.uniba.it
Francesco
F
Berardi
Carmen
C
Abate
Savina
S
Ferorelli
Vincenzo
V
Uricchio
Nicola A
NA
Colabufo
Mauro
M
Niso
Roberto
R
Perrone
D000577:Amides / Q000737:chemistry; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008297:Male; D009281:Naphthalenes / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D009584:Nitrogen / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017480:Receptors, sigma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013251:Steroid Isomerases / Q000378:metabolism; D013329:Structure-Activity Relationship
C505382:1-cyclohexyl-4-(3-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-propyl)-piperazine; D000577:Amides; D008024:Ligands; D009281:Naphthalenes; D010879:Piperazines; D017480:Receptors, sigma; C106107:sigma-2 receptor; D013251:Steroid Isomerases; C090445:EBP protein, human; D009584:Nitrogen