Editorial

The concept of sigma receptors or sigma binding sites emerged in the late seventies out of the field of opiate receptor research, when the dysphoric effects of several new opiate drugs could not sufficiently be explained by interaction with one of the known opiate receptors. Originally proposed as an additional subtype of opiate receptors it was soon recognized that the newly designed sigma site was distinct from the different subtypes of opiate receptors (typical G-protein coupled membrane receptors) but seemed to represent first candidates of a new class of drug binding sites with rather atypical localization (largely intracellularly), of unknown transduction mechanism and with rather obscure cellular functions. Similarly, their pharmacological relevance remained in dispute.

Besides these open questions, sigma sites attracted increasing interest when it was shown that several psychotropic drugs were bound with considerable affinity to these sites. A specific case were the antipsychotics like haloperidol which were shown to bind nearly as potently to the sigma as to D2 sites. This observation led to the development of putative antipychotics with high sigma affinity but with low D2 blocking activity. Several such ligands were tested, but although they showed activity in pharmacological models indicative for antipsychotic activity, initial clinical trials with these drugs were disappointing. Accordingly, most companies stopped further development and the whole field of sigma site research lost its initial impact.

However, observations that some newer antidepressant drugs, such as sertraline, are also potent sigma ligands together with new preclinical findings regarding structure, cellular function, including putative endogenous ligands of sigma sites, again initiated the search for new sigma ligands as putative psychotropic drugs, the major effort being directed toward new antidepressants and anxiolytics. Some of those newly developed sigma ligands showed quite interesting properties in preclinical experiments and initial clinical trials. Together with findings concerning the possible role of sigma sites for the appetitive effects of cocaine, with evidence for cognition improving effects and the putative antidepressant effects of sigma ligands in models of neurodegenerative disorders, initial findings, of the specific antidepressant activity of sigma ligands in degenerative conditions, the whole fields of sigma research again became of increasing interest.

Accordingly, it seemed appropriate to organize a meeting with leading experts in the sigma field to update the present role and to discuss the future perspectives of sigma ligands in neuropsychiatry, from preclinical findings to their possible clinical use. This meeting took place within the framework of the ”Biocenter Symposium on Drug Therapy” series on November 21, 2003 at the Biocenter of the J.W. Goethe University Frankfurt. We are pleased to present the proceedings of this symposium in the present supplement issue of Pharmacopsychiatry. We would like to thank the authors for the excellent contributions and Novartis Pharma GmbH (Nurenberg, Germany) for an educational grant which made the symposium and the publication possible.

Frankfurt and Galway, October 2004