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Merck

2-Aminopyridine derivatives as potential σ(2) receptor antagonists.

ChemMedChem (2012-08-15)
Carmen Abate, Savina Ferorelli, Mauro Niso, Cesarea Lovicario, Vittoria Infantino, Paolo Convertini, Roberto Perrone, Francesco Berardi
ABSTRACT

σ(2) Receptor research is receiving increasing interest with regard to the potential of σ(2) proteins as targets for tumor therapy and diagnosis. Nevertheless, knowledge about the σ(2) receptor is far from conclusive. The paucity and modest affinity of known σ(2) antagonists represent one of the limitations to σ(2) receptor research. Previous studies of the high-affinity σ(2) agonist 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine 4 (PB28) suggested that a decrease in lipophilicity might lead to σ(2) ligands devoid of antiproliferative activity (potential σ(2) antagonists). With the aim of producing σ(2) receptor antagonists, we replaced the tetralin nucleus of compound 4 with a 2-aminopyridine moiety. A series of compounds with high affinity for both σ subtypes and with no antiproliferative activity in various cells (mouse HT-22, human SK-N-SH, MCF-7wt, and MCF-7σ(1)) were obtained. The effect on Ca(2+) mobilization was investigated for high-affinity compounds 18 and 4, which showed opposite effects. All of the data support the new 2-aminopyridines as high-affinity σ ligands with σ(2) antagonist and σ(1) agonist activity, and, despite the lack of significant σ(2) versus σ(1) selectivity, these novel compounds may be better tools for σ receptor research than the known low-affinity σ(2) antagonists.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Bromocyclopropane, 99%
Sigma-Aldrich
Palladium on activated charcoal, 10% Pd basis
Sigma-Aldrich
Palladium, sulfided, extent of labeling: 5 wt. % loading (dry basis), matrix activated carbon, wet support, (wet)