Design, synthesis, and biological evaluation of sigma receptors (σRS) ligands as potential pharmacotherapy for cancer and drug addiction

Sigma receptors are a well-defined unique class of receptors and are highly expressed in the central nervous system and also widely distributed in peripheral organs and tissues. There are two subtypes of sigma receptors: sigma-1 and sigma-2. These receptors are thought to be associated with functions and disorders such as inflammation, depression, anxiety, Alzheimer’s disease, epilepsy and drug abuse. The sigma-1 receptor has been demonstrated to be involved in acute and chronic effects of cocaine and methamphetamine toxicities. However, the role of sigma-2 receptors is less clear due to the lack of availability of detailed protein structural information and truly selective sigma-2 ligands, which hindered the pharmacological characterization of the sigma-2 subtype. In fact, the sigma-2 receptor has not yet been cloned. Several reports indicated that the activation of sigma-2 receptor also induces growth arrest and cell death in various tumor cell lines. This gives sigma-2 ligands possible application as effective agents for the treatment of cancer. In this regard, searching for selective, high affinity sigma-2 ligands led to the design and synthesis a series of isothiocyanate compounds derived from a selective sigma-2 compounds developed in our laboratory as selective irreversible sigma-2 ligands. Also, in the search for an effective drug for the treatment of cocaine abuse and addiction, and based on our previous work on CM699 that shoits ability to attenuate the cocaine self-administration. We have found that stimulant self-administration (cocaine or methamphetamine) was blocked by dual inhibition of the DAT and sigma-receptors However, CM699 had short half lives in Human and Rat liver microsomes assays (in vitro), and in rat in vivo assay. Although CM699 had a half-life of 4.4 hr in rat, a compound with utility as a treatment for stimulant abuse will need a longer half-life, achieved either by structural change or by formulation. In this regard, we have made more analogs of CM699 in order to enhance blockade of cocaine self-administration and metabolic stability. Additionally, in an effort to continue to develop highly selective sigma ligands, we have synthesized a novel series of benzofuran-based ligands, and more analogs of the highly selective sigma-1, CM304