Sigma-1 receptor ligand PD144418 and sigma-2 receptor ligand YUN-252 attenuate the stimulant effects of methamphetamine in mice

Tapia, Melissa A.; Lever, John R.; Lever, Susan Z.; Will, Melissa L.; Park, Eric S.; Miller, Dennis K.

doi:10.1007/s00213-019-05268-2

Cited by 6 publications

(3 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The finding that COC had a relatively higher binding affinity than METH, but could not form a stable salt bridge with Glu172, indicated that METH may exhibit a different mode of action from COC with respect to σ1R. The antagonist GMJ displayed the highest binding affinity to σ1R, which seemed in line with experimental findings that high-affinity and selective σ1 antagonists could be used to attenuate METH-induced stimulant and neurotoxic effects (Kaushal, Seminerio, et al, 2011;Matsumoto et al, 2008;Tapia et al, 2019). It is well recognized that σ1R can accommodate diverse ligands (Yano et al, 2018); however, the binding of different ligands yielded different effects on σ1R conformations.…”

Section: Meth Showed a Low Binding Affinity To σ1r And A Binding Pose Different From Other Ligandssupporting

confidence: 76%

Association of sigma‐1 receptor with dopamine transporter attenuates the binding of methamphetamine via distinct helix–helix interactions

Chen

2021

Chem Biol Drug Des

View full text Add to dashboard Cite

Dopamine transporter (DAT) and sigma‐1 receptor (σ1R) are potential therapeutic targets to reduce the psychostimulant effects induced by methamphetamine (METH). Interaction of σ1R with DAT could modulate the binding of METH, but the molecular basis of the association of the two transmembrane proteins and how their interactions mediate the binding of METH to DAT or σ1R remain unclear. Here, we characterize the protein–ligand and protein–protein interactions at a molecular level by various theoretical approaches. The present results show that METH adopts a different binding pose in the binding pocket of σ1R and is more likely to act as an agonist. The relatively lower binding affinity of METH to σ1R supports the role of antagonists as inhibitors that protect against METH‐induced effects. We demonstrate that σ1R could bind to Drosophila melanogaster DAT (dDAT) through interactions with either the transmembrane helix α12 or α5 of dDAT. Our results showed that the truncated σ1R displays stronger association with dDAT than the full‐length σ1R. Although different helix–helix interactions between σ1R and dDAT lead to distinct effects on the dynamics of individual protein, both associations attenuate the binding affinity of METH to dDAT, particularly in the interactions with the helix α5 of dDAT. Together, the present study provides the first computational investigation on the molecular mechanism of coupling METH binding and the association of σ1R with dDAT.

show abstract

Section: Meth Showed a Low Binding Affinity To σ1r And A Binding Pose Different From Other Ligandssupporting

confidence: 76%

Association of sigma‐1 receptor with dopamine transporter attenuates the binding of methamphetamine via distinct helix–helix interactions

Chen

2021

Chem Biol Drug Des

View full text Add to dashboard Cite

show abstract

“…These effects were in accordance with literature demonstrating that S1R antagonists produce neither conditioned place preference nor conditioned place aversion [ 26 ]. While the exact mechanism of S1R antagonist activity requires further investigation, an interaction with reward circuitry has been inferred from reports where S1R antagonist treatment blocks sensitization to the locomotor effects of methamphetamine [ 50 ], cocaine-seeking behavior and neurotoxicity [ 51 ]. Although beyond the scope of the current characterization, further investigation is warranted to evaluate if SI 1/28 modulates the reinforcing effects of methamphetamine and cocaine as reported in the presence of other S1R antagonists.…”

Section: Discussionmentioning

confidence: 99%

Examination of the Novel Sigma-1 Receptor Antagonist, SI 1/28, for Antinociceptive and Anti-allodynic Efficacy against Multiple Types of Nociception with Fewer Liabilities of Use

Wilson

Eans

Ramadan-Siraj

et al. 2022

IJMS

View full text Add to dashboard Cite

Neuropathic pain is a significant problem with few effective treatments lacking adverse effects. The sigma-1 receptor (S1R) is a potential therapeutic target for neuropathic pain, as antagonists for this receptor effectively ameliorate pain in both preclinical and clinical studies. The current research examines the antinociceptive and anti-allodynic efficacy of SI 1/28, a recently reported benzylpiperazine derivative and analog of the S1R antagonist SI 1/13, that was 423-fold more selective for S1R over the sigma-2 receptor (S2R). In addition, possible liabilities of respiration, sedation, and drug reinforcement caused by SI 1/28 have been evaluated. Inflammatory and chemical nociception, chronic nerve constriction injury (CCI) induced mechanical allodynia, and adverse effects of sedation in a rotarod assay, conditioned place preference (CPP), and changes in breath rate and locomotor activity were assessed after i.p. administration of SI 1/28. Pretreatment with SI 1/28 produced dose-dependent antinociception in the formalin test, with an ED50 (and 95% C.I.) value of 13.2 (7.42–28.3) mg/kg, i.p. Likewise, SI 1/28 produced dose-dependent antinociception against visceral nociception and anti-allodynia against CCI-induced neuropathic pain. SI 1/28 demonstrated no impairment of locomotor activity, conditioned place preference, or respiratory depression. In summary, SI 1/28 proved efficacious in the treatment of acute inflammatory pain and chronic neuropathy without liabilities at therapeutic doses, supporting the development of S1R antagonists as therapeutics for chronic pain.

show abstract

“…With respect to psychostimulant reward behaviors, S1R antagonists block locomotor reactivity and behavioral sensitization to both cocaine and methamphetamine [ 55 , 61 , 64 , 72 , 73 ], and these effects are recapitulated by genetic downregulation of S1R [ 61 ]. In animals trained to exhibit a conditioned place preference for cocaine (CPP), S1R agonists reinstate extinguished CPP, whereas the S1R antagonists NE-100 and BD1047 block the expression of CPP induced by a priming injection of cocaine [ 65 ].…”

Section: S1r As a Modulator Of The Rewarding Properties Of Drugs Of A...mentioning

confidence: 99%

Recent advances in drug discovery efforts targeting the sigma 1 receptor system: Implications for novel medications designed to reduce excessive drug and food seeking

Knowles,

Armanious,

Peng

et al. 2023

Addiction Neuroscience

View full text Add to dashboard Cite

Sigma-1 receptor ligand PD144418 and sigma-2 receptor ligand YUN-252 attenuate the stimulant effects of methamphetamine in mice

Cited by 6 publications

References 56 publications

Association of sigma‐1 receptor with dopamine transporter attenuates the binding of methamphetamine via distinct helix–helix interactions

Association of sigma‐1 receptor with dopamine transporter attenuates the binding of methamphetamine via distinct helix–helix interactions

Examination of the Novel Sigma-1 Receptor Antagonist, SI 1/28, for Antinociceptive and Anti-allodynic Efficacy against Multiple Types of Nociception with Fewer Liabilities of Use

Recent advances in drug discovery efforts targeting the sigma 1 receptor system: Implications for novel medications designed to reduce excessive drug and food seeking

Contact Info

Product

Resources

About