Sigma receptors mediate the psychotomimetic effects of N-allylnormetazocine (SKF-10,047), but not its opioid agonistic-antagonistic properties

Khazan, N.; Young, Gerald A.; El-Fakany, E.E.; Hong, O.; Calligaro, David O.

doi:10.1016/0028-3908(84)90015-7

Cited by 46 publications

(19 citation statements)

References 3 publications

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“…These effects are similar to those seen in phencyclidine (PCP or "angel dust") intoxication (3). In addition, benzomorphans and PCP have similar behavioral and autonomic effects in animals (4)(5)(6)(7)(8)(9).…”

supporting

confidence: 62%

Identification of the binding subunit of the sigma-type opiate receptor by photoaffinity labeling with 1-(4-azido-2-methyl[6-3H]phenyl)-3-(2-methyl[4,6-3H]phenyl)guanidine.

Kavanaugh

Tester

Scherz

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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The r-type opiate receptor is a distinct binding site in the brain that may mediate some of the psychotomimetic effects caused by benzomorphan opiates and phencyclidine in humans. We have developed a synthetic, highly selective ligand for this receptor, 1,3-di-o-tolylguanidine (DTG). To identify the binding protein(s) of the or receptor, we have now synthesized a radiolabeled azide derivative of DTG,

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supporting

confidence: 62%

Identification of the binding subunit of the sigma-type opiate receptor by photoaffinity labeling with 1-(4-azido-2-methyl[6-3H]phenyl)-3-(2-methyl[4,6-3H]phenyl)guanidine.

Kavanaugh

Tester

Scherz

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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“…Based on the psychotomimetic effects of (±)-SKF-10,047 (N-allylnormetazocine) and related benzomorphans which were not reversed by opioid antagonists, Martin and coworkers named this distinct class of receptor as " sigma," [72] derived from the first letter "S" from SKF-10,047. Subsequent studies with the (+) and (-) enantiomers of SKF-10,047 revealed that the (-)-isomer was responsible for the majority of opioidmediated effects that were specifically antagonized by classical opioid antagonists such as naltrexone (Table 3) [73,74]. However, (+)-SKF-10,047 produced actions that were insensitive to classical opioid antagonists [75][76][77].…”

Section: Sigma Receptorsmentioning

confidence: 99%

Sigma Receptors and Cocaine Abuse

Narayanan¹,

Mésangeau²,

Poupaert³

et al. 2011

CTMC

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Sigma receptors have been well documented as a protein target for cocaine and have been shown to be involved in the toxic and stimulant actions of cocaine. Strategies to reduce the access of cocaine to sigma receptors have included antisense oligonucleotides to the sigma-1 receptor protein as well as small molecule ligand with affinity for sigma receptor sites. These results have been encouraging as novel protein targets that can attenuate the actions of cocaine are desperately needed as there are currently no medications approved for treatment of cocaine toxicity or addiction. Many years of research in this area have yet to produce an effective treatment and much focus was on dopamine systems. A flurry of research has been carried out to elucidate the role of sigma receptors in the blockade of cocaine effects but this research has yet to yield a clinical agent. This review summarizes the work to date on the linkage of sigma receptors and the actions of cocaine and the progress that has been made with regard to small molecules. Although there is still a lack of an agent in clinical trials with a sigma receptor mechanism of action, work is progressing and the ligands are becoming more selective for sigma systems and the potential remains high.

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“…both (+) and (-)-isomers of the compounds) were used in the experiments. Further investigations with enantiomerically pure probe compounds showed that the (+)-isomer of SKF-10,047 produces actions that were not sensitive to opioid antagonists [Vaupel 1983], whereas SKF-10,047 (-)-isomers were sensitive to these antagonists [Young and Khazan, 1984; Khazan et al, 1984]. Thus, Sig1R prefers (+)-benzomorphans, while true opioid receptors bind with high affinity only to (-)-enantiomers.…”

Section: Introductionmentioning

confidence: 99%

Sigma 1 receptor: A novel therapeutic target in retinal disease

Smith

Wang

Cui

et al. 2018

Progress in Retinal and Eye Research

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Retinal degenerative diseases are major causes of untreatable blindness worldwide and efficacious treatments for these diseases are sorely needed. A novel target for treatment of retinal disease is the transmembrane protein Sigma 1 Receptor (Sig1R). This enigmatic protein is an evolutionary isolate with no known homology to any other protein. Sig1R was originally thought to be an opioid receptor. That notion has been dispelled and more recent pharmacological and molecular studies suggest that it is a pluripotent modulator with a number of biological functions, many of which are relevant to retinal disease. This review provides an overview of the discovery of Sig1R and early pharmacologic studies that led to the cloning of the Sig1R gene and eventual elucidation of its crystal structure. Studies of Sig1R in the eye were not reported until the late 1990s, but since that time there has been increasing interest in the potential role of Sig1R as a target for retinal disease. Studies have focused on elucidating the mechanism(s) of Sig1R function in retina including calcium regulation, modulation of oxidative stress, ion channel regulation and molecular chaperone activity. Mechanistic studies have been performed in isolated retinal cells, such as Müller glial cells, microglial cells, optic nerve head astrocytes and retinal ganglion cells as well as in the intact retina. Several compelling studies have provided evidence of powerful in vivo neuroprotective effects against ganglion cell loss as well as photoreceptor cell loss. Also described are studies that have examined retinal structure/function in various models of retinal disease in which Sig1R is absent and reveal that these phenotypes are accelerated compared to retinas of animals that express Sig1R. The collective evidence from analysis of studies over the past 20 years is that Sig1R plays a key role in modulating retinal cellular stress and that it holds great promise as a target in retinal neurodegenerative disease.

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Sigma receptors mediate the psychotomimetic effects of N-allylnormetazocine (SKF-10,047), but not its opioid agonistic-antagonistic properties

Cited by 46 publications

References 3 publications

Identification of the binding subunit of the sigma-type opiate receptor by photoaffinity labeling with 1-(4-azido-2-methyl[6-3H]phenyl)-3-(2-methyl[4,6-3H]phenyl)guanidine.

Identification of the binding subunit of the sigma-type opiate receptor by photoaffinity labeling with 1-(4-azido-2-methyl[6-3H]phenyl)-3-(2-methyl[4,6-3H]phenyl)guanidine.

Sigma Receptors and Cocaine Abuse

Sigma 1 receptor: A novel therapeutic target in retinal disease

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