Editorial [Hot topic: Sigma1 and Sigma 2 Receptors (Guest Editor: Richard A. Glennon)]

It was more than 15 years ago that we first reviewed the “sigma enigma” [1]. At that time sigma (??) receptors represented a novel binding protein for which agents from an assortment of therapeutic classes and drugs of abuse displayed affinity. Indeed, the receptors seemed quite promiscuous because they displayed (at least micromolar) affinity for a very large number of agents encompassing a wide variety of structure-types: from simple arylalkylamines to more structurally complex, polycyclic cyclopentanoperhydrophenanthrenes. The receptors were initially thought to be a type of opioid receptor. Today, sigma receptors still remain somewhat of an enigma because relatively little is known about their structural composition and/or functionality (e.g. transduction mechanisms or second messenger systems), and what little is known suggests they are very different from most other recognized receptor types. On the other hand, various agents with nanomolar, and even sub-nanomolar, affinity now have been identified and pharmacophore models have been proposed that are in the process of being further defined, or re-defined. Sigma receptors offer a window of understanding to totally unique types of receptor proteins. In 1976, examining the actions of various opiates in the chronic spinal dog, Martin and colleagues proposed the existence of several distinct types of opioid receptors [2]. The actions of morphine were attributed to activation of a set of receptors to which the name μ-opioid receptors (now, MORs) was applied, whereas those of ketocyclazocine were ascribed to a different class of opioid receptors termed κ-opioid receptors (now, KORs). The benzomorphan SKF-10,047 (N-allylnormetazocine; NANM), although displaying some antagonist properties at μ-opioid receptors, produced effects distinct from those of morphine and ketocyclazocine. To account for these actions, SKF-10,047 was designated as an early prototypic agonist ligand for “sig-opioid” receptors. During the following decade it gradually became apparent that various non-opiate ligands display high affinity for these receptors, that the stereochemistry of benzomorphans preferred by sig receptors was usually the reverse of what was preferred by μ and κ receptors, and that sig receptor pharmacology was quite distinct from that of the other opioid receptors. Eventually, the “sig-opioid” receptors were effectively divorced from the opioid receptor family. Subsequently, NANM and several related benzomorphans were found to bind at sites displaying high affinity for phencyclidine (PCP) and, for a while, these sites were termed PCP/sig (or sig/PCP) receptors. Due to differences in the brain localization of these binding proteins, and because the antipsychotic agent haloperidol possessed high affinity for some PCP/sig sites but not for others, terms such as “haloperidol-sensitive” and “haloperidol-insensitive” sig sites began to appear in the literature. It is now recognized that sig sites are distinct from PCP sites, and that haloperidol binds at sig receptors but displays lower affinity for PCP receptors. Another ligand found to differentiate these sites was di-o-tolylguanidine (DTG) which was introduced in the mid 1980s. This agent, and its tritiated version, [3H]DTG, are still in use today. Various antipsychotic agents (e.g. phenothiazines, thioxanthenes, butyrophenones) were found to bind at sig receptors (although not necessarily with very high affinity) leading to early speculation that selective sig ligands might represent a novel class of agents for the treatment of schizophrenia. Rimcazole (with micromolar affinity for sig receptors) was the first sig ligand to enter clinical trials, but studies were terminated shortly thereafter. Today it is realized that rimcazole is a weak sig receptor antagonist with high affinity for the dopamine transporter [3]. This, coupled with the use of different membrane preparations and animal species, different radioligands, lack of appropriate functional assays, and an initial lack of awareness of receptor heterogeneity (see below), temporarily dampened enthusiasm for sig receptor research.