Sigma receptors: biology and therapeutic potential

Abstract

More than 20 years after the identification of the sigma receptors as a unique binding site in the brain and in the peripheral organs, several questions regarding this receptor are still open. Only one of the subtypes of the receptor has been cloned to date, but the endogenous ligand still remains unknown, and the possible association of the receptor with a conventional second messenger system is controversial. From the very beginning, the sigma receptors were associated with various central nervous system disorders such as schizophrenia or movement disorders. Today, after hundreds of papers dealing with the importance of sigma receptors in brain function, it is widely accepted that sigma receptors represent a new and different avenue in the possible pharmacological treatment of several brain-related disorders. In this review, what is known about the biology of the sigma receptor regarding its putative structure and its distribution in the central nervous system is summarized first. The role of sigma receptors regulating cellular functions and other neurotransmitter systems is also addressed, as well as a short overview of the possible endogenous ligands. Finally, although no specific sigma ligand has reached the market, different pharmacological approaches to the alleviation and treatment of several central nervous system disorders and deficits, including schizophrenia, pain, memory deficits, etc., are discussed, with an overview of different compounds and their potential therapeutic use.

Effects of UMB24 and (±)-SM 21, putative σ2-preferring antagonists, on behavioral toxic and stimulant effects of cocaine in mice

“…In addition, the relative selectivities of UMB24 and (±)-SM 21 were determined for dopamine, opioid, and phencyclidine sites on NMDA receptors because many historic σ receptor ligands interact with them (Guitart et al, 2004). The affinities of these compounds for 5-HT 2 receptors were also examined because antagonists at these sites are capable of attenuating the toxicity of cocaine (Ritz and George, 1997).…”

“…σ Receptors are unique proteins with an amino acid sequence, drug selectivity pattern, and anatomical distribution that is distinctly different from other mammalian proteins (Guitart et al, 2004;Matsumoto et al, 2003). There are two established subtypes, σ 1 and σ 2 , which are localized in many motor, limbic, and endocrine regions of the brain (Bouchard and Quirion, 1997).…”

<![CDATA[Binding characteristics of sigma2 receptor ligands]]>

“…The benzomorphan (+)pentazocine displays several hundred-fold selectivity for the former whereas DTG binds nearly equally well at both populations. The σ 1 receptor has been recently cloned from several sources including human brain; σ 2 receptors have yet to be cloned (reviewed: Guitart et al, 2004). A very recent review (Guitart et al, 2004) describes the potential involvement of σ receptors in schizophrenia, movement disorders, depression, anxiety, drug abuse, and pain.…”

“…The σ 1 receptor has been recently cloned from several sources including human brain; σ 2 receptors have yet to be cloned (reviewed: Guitart et al, 2004). A very recent review (Guitart et al, 2004) describes the potential involvement of σ receptors in schizophrenia, movement disorders, depression, anxiety, drug abuse, and pain. For general reviews of early investigations with σ receptors and σ receptor ligands, the reader is referred to: Abou-Gharbia et al, 1993;Chavkin, 1990;Domino and Kamenka, 1988;Itzhak, 1994;Itzhak and Stein, 1990;Junien and Leonard, 1989;Musacchio et al, 1989;Quirion et al, 1987;Snyder and Largent, 1989;Walker et al, 1990.…”

Role of Sigma Receptor and Neurosteroids in Pain Sensation

“…6 이러한 시그마-1 수용체는 학습과 기 억 이상, 우울증, 정신분열증, 및 약물남용과 같은 중추신경 계 내의 다양한 신경 생리학적 현상에서 중요한 역할을 담당 한다. 4,7,8 시그마-1 수용체의 내인성 리간드는 아직까지 정확히 규명 되지 않은 상태이며, trace amine과 환각성 물질인 dimethyltryptamine (DMT)와 같은 체내 물질들이 내인성 리간 드로 작용할 것으로 추측된다. 9 그 중 pregnenolone 및 dehydroepiandrosterone (DHEA)을 포함한 신경스테로 이드도 시그마-1 수용체를 활성화 시키는 내인성 리간드로 작용하는 것으로 보고 되었다.…”