Pharmacology of Drugs Used as Stimulants

Docherty, James R.; Alsufyani, Hadeel A.

doi:10.1002/jcph.1918

Cited by 40 publications

(38 citation statements)

References 177 publications

(279 reference statements)

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“…1g), respectively, thus indicating that both methamphetamine and cocaine compete for [ 3 H]paroxetine binding, consistent with the psychostimulants binding to the central site. The potency of methamphetamine and cocaine on nSERT differs by a factor of ∼1,000, in accord with previous studies, whereas the two ligands are equally potent on DAT 48 , underscoring the differences in residue composition and plasticity of the central binding pockets of SERT and DAT. Taken together, the ligand binding data illustrate that our purification method yields native transporter fully active in ligand binding.…”

Section: Resultssupporting

confidence: 87%

Structures and membrane interactions of native serotonin transporter in complexes with psychostimulants

Yang

Zhao

Tajkhorshid

et al. 2022

Preprint

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The serotonin transporter (SERT) is a member of the SLC6 neurotransmitter transporter family that mediates serotonin reuptake at presynaptic nerve terminals. SERT is the target of both therapeutic antidepressant drugs and illicit psychostimulant substances such as cocaine and methamphetamines, which are small molecules that perturb normal serotonergic transmission by interfering with serotonin transport. Despite decades of studies, the oligomerization state of native SERT (nSERT) and its interactions with potential proteins remain unresolved. Here we develop methods to isolate nSERT from porcine brain, utilize fluorescence-detection size-exclusion chromatography to investigate the nSERT oligomerization state, and report single-particle cryo-electron microscopy structures of nSERT in complexes with methamphetamine and cocaine, providing structural insights into psychostimulant recognition and accompanying nSERT conformations. Methamphetamine and cocaine both bind to SERT central site, stabilizing the transporter in outward and outward-occluded conformations, respectively. We also identify densities attributable to multiple cholesterol molecules, as well as to a potential polyunsaturated lipid bound to SERT allosteric site. Our study establishes that nSERT is best described as a monomeric entity, isolated without interacting proteins, and is ensconced by multiple cholesterol and lipid molecules.

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Section: Resultssupporting

confidence: 87%

Structures and membrane interactions of native serotonin transporter in complexes with psychostimulants

Yang

Zhao

Tajkhorshid

et al. 2022

Preprint

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“…Specifically, the amphetamines act as substrates and competitive inhibitors of monoamine transporters (DAT, NET and SERT) that normally function to rapidly remove neurotransmitters from the synapse after they are released by vesicles (Docherty and Alsufyani, 2021;McCreary et al, 2015;Rothman et al, 2001;Rothman and Baumann, 2003). Through intracellular actions in the presynaptic neuron at vesicular monoamine transporter 2 (VMAT2), trace amine associated receptor 1 (TAAR1), and other target sites, amphetamines increase cytosolic concentrations of monoamines and cause the reversal of transporter activity to promote efflux of transmitters into the synapse.…”

Section: Discussionmentioning

confidence: 99%

Amphetamines Exacerbate then Ameliorate Respiratory Effects of Fentanyl as Their Dose Increases

Elder

Varshneya

Walentiny

et al. 2022

Preprint

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Background and Purpose: The opioid epidemic remains one of the most pressing public health crises facing the United States. Rising rates of opioid-involved overdose deaths are presently driven primarily by fentanyl and related synthetic opioid agonists that are resistant to reversal by naloxone and increasingly used as adulterants or clandestine substitutes in illicitly produced opioids, sedatives, and psychostimulants. Deaths involving opioids typically result from lethal respiratory depression and it is currently unknown whether co-use of psychostimulants with opioids affects respiratory toxicity. Considering psychostimulant overdoses have increased over 3-fold since 2013, and half of those co-involved opioids, this is a cardinal question. Experimental Approach: Naloxone, d-amphetamine (AMPH), and (+/-)-methamphetamine (METH), were evaluated for their effects on basal and fentanyl-depressed respiration. Minute volume (MVb) was measured in awake, freely moving mice via whole-body plethysmography to quantify fentanyl-induced respiratory depression and its modulation by dose ranges of each test drug. Key Results: Naloxone reversed respiratory depression induced by fentanyl only at the highest dose tested (10 mg•kg-1). Both AMPH and METH exhibited bidirectional effects on MVb under basal conditions, producing depressions then elevations of respiration as dose increased. Under depressed conditions the bidirectional effects of AMPH and METH on respiration were exaggerated, exacerbating and then reversing fentanyl-induced depression as dose increased. Conclusions and Implications: These results indicate that co-use of amphetamines with fentanyl may worsen respiratory depression, but conversely, monoaminergic components of the amphetamines may possibly be exploited to mitigate fentanyl overdose.

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“…In addition, the effects can be derived from the two mechanisms combined [ 68 ]. Regardless of the molecular mechanism involved, all synthetic cathinones increase extracellular monoamine concentrations in the brain, enhancing cell-to-cell monoamine signalling, and are potent inhibitors of NA transporter (NET) [ 69 ]. However, they differ in their inhibition profiles on DA transporter (DAT) and 5-HT transporter (SERT) and in their ability to release monoamines, which possibly explains clinical differences reported in their effects and toxicities [ 68 , 70 , 71 , 72 ].…”

Section: Therapeutic Potential Of Synthetic Cathinones and Synthetic ...mentioning

confidence: 99%

“…This medicine is still an approved medication by the FDA. However, it is a Schedule V controlled substance and is rarely prescribed [ 69 ].…”

Section: Therapeutic Potential Of Synthetic Cathinones and Synthetic ...mentioning

confidence: 99%

“…Synthetic cathinones were primarily synthesized for therapeutic purposes. However, all synthetic cathinones, excepting bupropion, branded as Wellbutrin [ 41 , 81 ], and amphepramone, branded as Tenuate and Hipofagin, were withdrawn from the market due to vast cases of dependency and associated toxicity [ 69 ].…”

Section: Toxicity Of Synthetic Cathinones and Synthetic Cannabinoidsmentioning

confidence: 99%

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Novel Psychoactive Substances: The Razor’s Edge between Therapeutical Potential and Psychoactive Recreational Misuse

et al. 2022

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Background: Novel psychoactive substances (NPS) are compounds of natural and synthetic origin, similar to traditional drugs of abuse. NPS are involved in a contemporary trend whose origin lies in a thinner balance between legitimate therapeutic drug research and legislative control. The contemporary NPS trend resulted from the replacement of MDMA by synthetic cathinones in ‘ecstasy’ during the 2000s. The most common NPS are synthetic cannabinoids and synthetic cathinones. Interestingly, during the last 50 years, these two classes of NPS have been the object of scientific research for a set of health conditions. Methods: Searches were conducted in the online database PubMed using boolean equations. Results: Synthetic cannabinoids displayed protective and therapeutic effects for inflammatory, neurodegenerative and oncologic pathologies, activating the immune system and reducing inflammation. Synthetic cathinones act similarly to amphetamine-type stimulants and can be used for depression and chronic fatigue. Conclusions: Despite the scientific advances in this field of research, pharmacological application of NPS is being jeopardized by fatalities associated with their recreational use. This review addresses the scientific achievements of these two classes of NPS and the toxicological data, ending with a reflection on Illicit and NPS control frames.

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Pharmacology of Drugs Used as Stimulants

Cited by 40 publications

References 177 publications

Structures and membrane interactions of native serotonin transporter in complexes with psychostimulants

Structures and membrane interactions of native serotonin transporter in complexes with psychostimulants

Amphetamines Exacerbate then Ameliorate Respiratory Effects of Fentanyl as Their Dose Increases

Novel Psychoactive Substances: The Razor’s Edge between Therapeutical Potential and Psychoactive Recreational Misuse

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