Abstract
Nearly 40 years after the first disclosure of sigma receptors, the sigma-2 (σ2) receptor was recently identified as the Transmembrane Protein 97 (TMEM97, also known as MAC30 (Meningioma-associated protein). This macromolecule has been associated with a number of disease states such as schizophrenia, Alzheimer’s disease, neuropathic pain, traumatic brain injury, and cancer. We have recently identified a series of novel, functionalized γ-butyrolactones that are potent σ2 receptor ligands that are drug-like and identified a potential candidate (9z) for future in vivo study.
Highlights
IntroductionMartin et al described their efforts to classify opioids based on their impact on chronic spinal dogs
We have recently identified a series of novel, functionalized γ-butyrolactones that are potent σ2 receptor ligands that are drug-like and identified a potential candidate (9z) for future in vivo study
Synthesis of substituted γ-butyrolactones was conducted as shown in Scheme 1 utilizing novel methods developed in our laboratory
Summary
Martin et al described their efforts to classify opioids based on their impact on chronic spinal dogs They observed that exposure to morphine (1), ketocyclazocine, (2), and (rac)-SKF-100047 (3) (Figure 1) produced different responses in this animal model. D. Bowen et al successfully demonstrated that there are two sub-types of this receptor, sigma-1 (σ1) and sigma-2 (σ2),[3] and in 1996 mammalian σ1 receptor was cloned and expressed in yeast cells.[4] A crystal structure of the human σ1 receptor was reported in 2016,5 but to date, there is no known natural ligand for this receptor
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