2-Aminopyridine Derivatives as Potential s2 Receptor Antagonists

s2 Receptor research is receiving increasing interest with regard to the potential of s2 proteins as targets for tumor therapy and diagnosis. Nevertheless, knowledge about the s2 receptor is far from conclusive. The paucity and modest affinity of known s2 antagonists represent one of the limitations to s2 receptor research. Previous studies of the high-affinity s2 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 s2 ligands devoid of antiproliferative activity (potential s2 antagonists). With the aim of producing s2 receptor antagonists, we replaced the tetralin nucleus of compound 4 with a 2-aminopyridine moiety. A series of compounds with high affinity for both s subtypes and with no antiproliferative activity in various cells (mouse HT-22, human SK-N-SH, MCF-7wt, and MCF-7s1) were obtained. The effect on Ca2+ 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 s ligands with s2 antagonist and s1 agonist activity, and, despite the lack of significant s2 versus s1 selectivity, these novel compounds may be better tools for s receptor research than the known low-affinity s2 antagonists.