To date, the research in the field of sigma receptors (sR) still remains difficult, considering the fact that
only the s1 subtype was purified and cloned from several animal species including man, while the s2R
subtype has not been cloned yet and still remains an unknown protein. Is well-known that s1R has been
associated with many diseases including stroke, cocaine addiction, pain, cancer, and neurodegenerative
pathologies1 while s2R subtype are overexpressed in several tumor cells. By these considerations the s1
ligands could be used as neuroprotective agents, while s2 ligands can be considered a tool for cancer
therapy and diagnosis (as PET or SPECT).
Starting from the structure of previously reported2, high-affinity benzoxazolone-based s1 ligands, the
three-dimensional homology model of the s1R was exploited for retrieving the molecular determinants to
fulfill the optimal pharmacophore requirements. Accordingly, the benzoxazolone moiety was replaced by
other heterocyclic scaffolds, the relevant conformational space in the s1R binding cavity was explored,
and the effect on s1R binding affinity was ultimately assessed. Next, the compounds designed in silico
were synthesized, and their affinity and selectivity toward s1 and s2 receptors were tested.
We designed and synthesized two new series of compounds 1a-h and 2a-h as potential sigma ligands. The highest s1 affinity (Ki= 16nM) was reached by compound 1a (R=H; R’= CH3); towards s2R the best
result was obtained by derivative 2h (R= 2,4(CH3)2; R’= cyclohexyl), with a Ki value of 80 nM.
