Structural manipulation on the catecholic fragment of dopamine D1 receptor agonist 1-phenyl-N-methyl-benzazepines

Zhang, Jing; Jian, Huang; Song, Zilan; Guo, Lin; Cai, Wenxian; Wang, Yun; Zhen, Xuechu; Zhang, Ao

doi:10.1016/j.ejmech.2014.07.059

Cited by 12 publications

(9 citation statements)

References 24 publications

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“…To further establish the role of sigma‐1 receptors in anti‐seizure activity and exclude the potential involvement of other receptors (D 1 , D 2 , 5‐HT 1A , etc), we synthesized several chemical derivatives of SKF83959 in order to find a selective sigma‐1 receptor allosteric modulator. One of these compounds, SOMCL‐668, did not exhibit affinities for human D 1 , D 2 , D 3 , 5‐HT 1A , 5‐HT 2A receptors (Zhang et al ., ), but showed a potent allosteric modulating activity on sigma‐1 receptors. As shown in Figure , SOMCL‐668 100 μM shifted the saturation curve toward the left, and significantly decreased the K D (dissociation constant of the radioligand) value (3.91 ± 0.35 nM vs. 7.24 ± 1.03 in control, P < 0.05, t ‐test).…”

Section: Resultsmentioning

confidence: 99%

Allosteric modulation of sigma‐1 receptors elicits anti‐seizure activities

Guo

Chen

Zhao

et al. 2015

British J Pharmacology

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Background and Purpose Application of orthosteric sigma‐1 receptor agonists as anti‐seizure drugs has been hindered by questionable efficacy and potential adverse effects. Here, we have investigated the anti‐seizure effects of the novel and potent allosteric modulator of sigma‐1 receptors, SKF83959 and its derivative SOMCL‐668 (3‐methyl‐phenyl‐2,3,4,5‐tetrahydro‐1H‐benzo[d]azepin‐7‐ol). Experimental Approach The anti‐seizure effects of SKF83959 were investigated in three mouse models, maximal electroshock seizures, pentylenetetrazole‐induced convulsions and kainic acid‐induced ‘status epilepticus’. Also, in rats, the cortical epileptiform activity induced by topical application of picrotoxin was recorded in electrocorticograms. In rat hippocampal brain slices, effects of the drugs on the high potassium‐evoked epileptiform local field potentials were studied. Anti‐seizure activities of SOMCL‐668, a newly developed sigma‐1 receptor selective allosteric modulator, were also investigated. Key Results SKF83959 (20, 40 mg·kg−1) exhibited anti –seizure actitity in the three mouse models and reduced the cortical epileptiform activity without alteration of spontaneous motor activity and motor coordination. These effects were blocked by the sigma‐1 receptor antagonist BD1047, but not the dopamine D1 receptor antagonist SCH23390. SKF83959 alone did not directly inhibit the epileptiform firing of CA3 neurons induced by high potassium in hippocampal slices, but did potentiate inhibition by the orthosteric sigma‐1 receptor agonist SKF10047. Lastly, a selective sigma‐1 receptor allosteric modulator SOMCL‐668, which does not bind to dopamine receptors, exerted similar anti‐seizure activities. Conclusions and Implications SKF83959 and SOMCL‐668 displayed anti‐seizure activities, indicating that allosteric modulation of sigma‐1 receptors may provide a novel approach for discovering new anti‐seizure drugs.

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Section: Resultsmentioning

confidence: 99%

Allosteric modulation of sigma‐1 receptors elicits anti‐seizure activities

Guo

Chen

Zhao

et al. 2015

British J Pharmacology

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“…Later, several chemical derivatives of SKF83959 were synthesized to find a selective Sig1R allosteric modulator and to exclude the potential involvement of other receptors. One of these newly synthesized compounds, called SOMCL-668 (Figure 2), did not exhibit affinity for human dopamine D 1 , D 2 , D 3 , serotonin 5-HT 1A , or 5-HT 2A receptors (Zhang et al, 2014) but did show potent allosteric modulating activity at Sig1R (Guo et al, 2015). Therefore, SOMCL-668 has also been proposed as a selective allosteric Sig1R modulator.…”

Section: Discovery Of Allosteric Sig1r Modulatorsmentioning

confidence: 99%

Allosteric Modulators of Sigma-1 Receptor: A Review

et al. 2019

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Allosteric modulators of sigma-1 receptor (Sig1R) are described as compounds that can increase the activity of some Sig1R ligands that compete with (+)-pentazocine, one of the classic prototypical ligands that binds to the orthosteric Sig1R binding site. Sig1R is an endoplasmic reticulum membrane protein that, in addition to its promiscuous high-affinity ligand binding, has been shown to have chaperone activity. Different experimental approaches have been used to describe and validate the activity of allosteric modulators of Sig1R. Sig1R-modulatory activity was first found for phenytoin, an anticonvulsant drug that primarily acts by blocking the voltage-gated sodium channels. Accumulating evidence suggests that allosteric Sig1R modulators affect processes involved in the pathophysiology of depression, memory and cognition disorders as well as convulsions. This review will focus on the description of selective and non-selective allosteric modulators of Sig1R, including molecular structure properties and pharmacological activity both in vitro and in vivo, with the aim of providing the latest overview from compound discovery approaches to eventual clinical applications. In this review, the possible mechanisms of action will be discussed, and future challenges in the development of novel compounds will be addressed.

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“…76–80 In an effort to ablate these off-target interactions, a series of modifications were performed, bringing to fruition SOMCL668, which exhibited no appreciable activity at the dopamine 1(D 1 ), D 2 , D 3 , 5-hydroxytryptamine 1A (HT), or 5-HT 2A receptors. 81,82 …”

Section: Sigma-1 Receptormentioning

confidence: 99%

“…76−80 In an effort to ablate these offtarget interactions, a series of modifications were performed, bringing to fruition SOMCL668, which exhibited no appreciable activity at the dopamine 1(D 1 ), D 2 , D 3 , 5-hydroxytryptamine 1A (HT), or 5-HT 2A receptors. 81,82 ■ HETERODIMERS GPCR homodimers and heterodimers have been observed in a variety of systems including tissues, cells that endogenously express both receptors, and in primary cell cultures. In some cases, it is critical for receptor function to form heteromeric pairs.…”

Section: ■ Dormentioning

confidence: 99%

Recent Advances in the Realm of Allosteric Modulators for Opioid Receptors for Future Therapeutics

Remesic

Hruby

Porreca

et al. 2017

ACS Chem. Neurosci.

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Opioids, and more specifically μ-opioid receptor (MOR) agonists such as morphine, have long been clinically used as therapeutics for severe pain states but often come with serious side effects such as addiction and tolerance. Many studies have focused on bringing about analgesia from the MOR with attenuated side effects, but its underlying mechanism is not fully understood. Recently, focus has been geared toward the design and elucidation of the orthosteric site with ligands of various biological profiles and mixed subtype opioid activities and selectivities, but targeting the allosteric site is an area of increasing interest. It has been shown that allosteric modulators play key roles in influencing receptor function such as its tolerance to a ligand and affect downstream pathways. There has been a high variance of chemical structures that provide allosteric modulation at a given receptor, but recent studies and reviews tend to focus on the altered cellular mechanisms instead of providing a more rigorous description of the allosteric ligand's structure–function relationship. In this review, we aim to explore recent developments in the structural motifs that potentiate orthosteric binding and their influences on cellular pathways in an effort to present novel approaches to opioid therapeutic design.

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Structural manipulation on the catecholic fragment of dopamine D1 receptor agonist 1-phenyl-N-methyl-benzazepines

Cited by 12 publications

References 24 publications

Allosteric modulation of sigma‐1 receptors elicits anti‐seizure activities

Allosteric modulation of sigma‐1 receptors elicits anti‐seizure activities

Allosteric Modulators of Sigma-1 Receptor: A Review

Recent Advances in the Realm of Allosteric Modulators for Opioid Receptors for Future Therapeutics

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