Synthesis and evaluation of sigma receptor ligands
Metadata[+] Show full item record
Sigma receptors are unique binding sites located in the central nervous system (CNS) and peripheral organs. Two sigma receptor subtypes (σ1 and σ2) have been described so far. It is known that the σ1 receptor is involved in a number of CNS disorders and the σ2 receptor is involved in tumor proliferation among others. Because of the important biological functions of the σ receptor, development of structure activity relationships (SAR) can aid in the identification of potential medications and imaging agents. Three series of analogs based on three lead compounds have been synthesized and evaluated for their in vitro affinity and selectivity for the σ1 and σ2 subtypes. Lead I is a selective σ1 receptor ligand with anti-cocaine activity, but its in vivo distribution is unknown. Our in vitro binding results showed that all the Lead I analogs are potent σ1 receptor ligands. Furthermore, one of the Lead I analogs was radioiodinated and evaluated for its in vivo distribution. In vivo evaluation of the radioiodinated Lead I analog has shown high brain uptake and specific binding to σ1 receptor of the radioligand. Lead II is also a selective σ1 receptor ligand and radioiodinated Lead II has been shown to be a potential imaging agent for the σ1 receptor. Two of the Lead II analogs were shown to be potent σ1 receptor ligands. The radioiodinated Lead II analogs were demonstrated to be potential imaging agents for σ1 receptor in vivo. Lead III is one of the most selective σ2 receptor ligands known to date. Only one of the newly synthesized Lead III analogs was found to be a selective σ2 receptor ligand. The SAR study of Lead III analogs successfully indentified the important structural features in Lead III for σ2 receptor binding. To summarize, the SAR studies based on the lead compounds have generated useful information and three potential σ1 imaging agents were prepared in the studies.