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2‐Aminopyridine Derivatives as Potential σ 2 Receptor Antagonists
Author(s) -
Abate Carmen,
Ferorelli Savina,
Niso Mauro,
Lovicario Cesarea,
Infantino Vittoria,
Convertini Paolo,
Perrone Roberto,
Berardi Francesco
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201200246
Subject(s) - lipophilicity , chemistry , agonist , receptor , intrinsic activity , antagonist , moiety , stereochemistry , partial agonist , lead compound , piperazine , pharmacology , in vitro , biochemistry , biology , organic chemistry
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.