Sigma Receptor LigandsIn this field of research, the group of W. Holzer collaborates with the University of Innsbruck (3D-QSAR, Prof. Thierry Langer) and the National Institutes of Health, Bethesda, MA (USA) (binding studies, Prof. Wayne D. Bowen)
Sigma receptors, of which there are at least two subtypes called 1 and 2, are proteins localized in the central nervous system, but also in endocrine, immune and reproductive tissues and tumor cell lines. Their biological role is not fully elucidated until now. Within the past few years, human, rat, and guinea-pig sigma-1 receptors have been cloned. However, the three-dimensional structure of these receptors remains unknown, leaving only structure activity relationship studies as methodical approaches for finding new selective ligands. Several psychoactive compounds such as haloperidol, phencyclidine, neurosteroids, benzomorphanes and cocaine have been shown to interact with sigma receptors. However, specific endogeneous ligands have not been found up to now. Sigma1-Receptors are regarded as possible clinical targets for the modulation of synthesis and release of various neurotransmitters, with the ligands also showing neuroprotective and antiamnesic activity. Sigma-2 receptor antagonists may help to ameliorate the motor side effects of neuroleptics, while sigma-2 receptor agonists may serve as antineoplastic agents and tools for non-invasive tumor imaging.
Aim of the project is to find more potent and subtype selective sigma receptor ligands by the use of pharmacophor models gained via 3D-QSAR. In this respect we focus our efforts in the systematic variation of known representatives of type A as well as in the development of new ligands based on a pyrazole core (B).