⫸STICKY⫷ The N&PD Recent Journal ARTICLE Club

[Nagelfar]

It’s a really interesting article, …
…
Definitely something I will be researching and looking into. Great post!

I think so as well. There's always odd discrepancies between dopaminergic drugs and their ability to cause addictive response. There's been attempts to separate the DA transporter ligands between "closed–to–out" versus "open–to–out" confirmations as indicators but those don't seem to be the difference.

Also direct receptor agonists of the dopamine receptor don't seem to be reinforcing in the same way, it has to do with dopamine released from, or impeded re-entry to, the transporter.

I know there is CART (cocaine–amphetamine regulated transcript) that might have to do with addiction. I wonder how that relates to the above considerations of "dopaminylation"?

 

[polymath]

A peptide with stimulant effects. I can't remember whether I've posted this in some thread earlier.

Terence K. Y. Lai, Ping Su, Hailong Zhang & Fang Liu, "Development of a peptide targeting dopamine transporter to improve ADHD-like deficits", Molecular Brain volume 11, Article number: 66 (2018)

Development of a peptide targeting dopamine transporter to improve ADHD-like deficits - Molecular Brain

Attention-deficit hyperactivity disorder (ADHD) is a neurocognitive disorder characterized by hyperactivity, inattention, working memory deficits and impulsivity. Its worldwide prevalence is estimated to be 3–5% in children and adolescents. The mainstay treatment for ADHD is stimulant...

molecularbrain.biomedcentral.com

Attention-deficit hyperactivity disorder (ADHD) is a neurocognitive disorder characterized by hyperactivity, inattention, working memory deficits and impulsivity. Its worldwide prevalence is estimated to be 3–5% in children and adolescents. The mainstay treatment for ADHD is stimulant medications (e.g. methylphenidate), which increase synaptic dopamine by directly blocking dopamine transporter (DAT). Although these pharmacological agents are effective, they are often associated with various side effects including risks for future substance use disorders in ADHD patients. Here, we investigated an interaction between DAT and dopamine D2 receptor (D2R) as a novel target to develop potential therapeutics for the treatment of ADHD by using an interfering peptide (TAT-DATNT) to dissociate this protein complex. We found that TAT-DATNT promotes locomotor behavior in Sprague-Dawley rats. Furthermore, using in vivo microdialysis and high-performance liquid chromatography, we found that the disruption of D2R-DAT elevates extracellular dopamine level. More importantly, the interfering peptide, TAT-DATNT, attenuates hyperactivity and improves spontaneous alternation behavior in spontaneously hypertensive rats (SHR) ------ a common animal model of ADHD. This work presents a different means (i.e. other than direct blockade by a DAT inhibitor) to regulate the activity of DAT and dopaminergic neurotransmission, and a potential target site for future development of ADHD treatments.

 

[sekio]

Not that its recent, but apparently lanthanum ion acts as an analgesic via a mu-opioid based mechanism.[ref] The caveat is it needs to be directly piped into the brain, past the BBB, to have such an effect. There is the usual problem (very generally speaking, charged compounds/ions of any sort need some sort of pump system to move across the BBB's lipid membranes) but also a unique reactivity/precipitation issue... lanthanum phosphate has incredibly low solubility. In fact lanthanym carbonate is prescribed as an oral phosphate binder for people with kidney failure and hyperphospnatemia. Lanthanum chloride solution is used to condition the water in swimmig pools as well, by sequestering phosphate as something insoluble, a major nutrient for algae/scum is greatly reduced, meaning less growth, and less need for large amounts of chlorinating agents.

 

[polymath]

Not that its recent, but apparently lanthanum ion acts as an analgesic via a mu-opioid based mechanism.[ref] The caveat is it needs to be directly piped into the brain, past the BBB, to have such an effect. There is the usual problem (very generally speaking, charged compounds/ions of any sort need some sort of pump system to move across the BBB's lipid membranes) but also a unique reactivity/precipitation issue... lanthanum phosphate has incredibly low solubility. In fact lanthanym carbonate is prescribed as an oral phosphate binder for people with kidney failure and hyperphospnatemia. Lanthanum chloride solution is used to condition the water in swimmig pools as well, by sequestering phosphate as something insoluble, a major nutrient for algae/scum is greatly reduced, meaning less growth, and less need for large amounts of chlorinating agents.

Then have to use trimethyllanthanum or some BBB penetrating nanoparticle formulation? Probably not a good idea if it can be neurotoxic like mercury.

Trimethyllanthanum | C3H9La | ChemSpider

Structure, properties, spectra, suppliers and links for: Trimethyllanthanum.

www.chemspider.com

 

[sekio]

So if La binds phosphate to form insoluble precipitate, and the brain has at least some phosphate hanging around (from hydrolysis of nucleoside polyphosphates, etc).... seems like there is a possibility for things to go fucky there. deposits of LaPO₄ crystallizing out in the subarachnoid space & loss of available phosphate reserves are two obvious possibilities as I see it

trimethyllanthanum has 1 paper on it and the title descries it as "elusive". probably not a drug candidate.

pumps that dose drugs to the CSF are quite doable - baclofen is one such drug dosed direct to CSF (for spasticity... I may have to get such a pump in future, depending on if my spasticity ggets worse )

 

[polymath]

Zinc ion concentration affects the dopamine transporter, but it's not clear whether this can be done with a non-toxic amount of zinc salts.

Zinc potentiates dopamine neurotransmission and cocaine seeking

Cocaine binds to the dopamine transporter (DAT) in the striatum to regulate cocaine reward and seeking behavior. Zinc (Zn2+) also binds to the DAT, but the in vivo relevance of this interaction is unknown. We found that cocaine abuse in humans correlated with low postmortem striatal Zn2+...

www.biorxiv.org

Dual Action of Zn2+ on the Transport Cycle of the Dopamine Transporter

Background: Zn[2+] was originally proposed to inhibit dopamine uptake by the dopamine transporter (DAT).Results: Zn[2+] depressed peak currents, and modulated steady state-currents through DAT in a manner dependent on internal Na[+] .Conclusion: At ...

www.ncbi.nlm.nih.gov

These results are the first to describe the involvement of synaptic Zn²⁺ in regulating DA neurotransmission as well as physiological and behavioral effects to cocaine and have important implications for both general DA-dependent behaviors and especially for the prevention and treatment of cocaine addiction. Specifically, our findings suggest that dietary Zn²⁺ intake, and potentially, impaired Zn²⁺ absorption or excretion mechanisms, are implicated in cocaine reward, seeking, and relapse.

 

[thegreenhand]

Does baclofen really have that low bioavailability when taken orally? I coulda swore my friend have a bottle of pills of baclofen but i could be wrong. A pump makes sense I just never realized that they would do it for that drug

 

[sekio]

Baclofen has good bioavailibility, but generally BA is determined by measuring the amount of drug absorbed into the bloodstream and not i.e. the brain or CSF.
Wiki sez: Intrathecal pumps offer much lower doses of baclofen because they are designed to deliver the medication directly to the spinal fluid rather than going through the digestive and blood system first. They are often preferred in spasticity patients such as those with spastic diplegia, as very little of the oral dose actually reaches the spinal fluid.

Likewise, intrathecal morphine is actually more effective than even IV morphine, again because only a portion of an administred dose crosses BBB and makes it to the brain/spinal cord.

There is also the benefit of not requiring to repeatedly dose oral medications, an intrathecal pump can provide constant levels of drug even when you're asleep.

 

[thegreenhand]

Ah thank you for the explanation! A "slow drip" is certainly always better i would imagine, hence the popular use of fentanyl patches in modern medicine

 

[Nagelfar]

"Chemists Develop a New Drug Discovery Strategy for “Undruggable” targets"

Chemists Develop a New Drug Discovery Strategy for “Undruggable” Targets
TOPICS:BiochemistryPharmaceuticalsThe University Of Hong Kong
By THE UNIVERSITY OF HONG KONG DECEMBER 29, 2020

DPAL
Graphic illustration of the work: DNA-programmed affinity labeling (DPAL) enables the direct screening of DNA-encoded chemical libraries (DELs) against membrane protein targets on live cells to create novel drug discovery opportunities. Credit: The University of Hong Kong

A research team led by Dr. Xiaoyu LI from the Research Division for Chemistry, Faculty of Science, in collaboration with Professor Yizhou LI from School of Pharmaceutical Sciences, Chongqing University and Professor Yan CAO from School of Pharmacy, Second Military Medical University in Shanghai has developed a new drug discovery method targeting membrane proteins on live cells.

Membrane proteins play important roles in biology, and many of them are high-value targets that are being intensively pursued in the pharmaceutical industry. The method developed by Dr. Li’s team provides an efficient way to discover novel ligands and inhibitors against membrane proteins, which remain largely intractable to traditional approaches. The development of the methodology and its applications are now published in Nature Chemistry, a prestigious chemistry journal by the Nature Publishing Group (NPG).

Cell Membrane DNA Tag
Artistic representation of the work: cell membrane is like a vast, complex, and unpredictable ocean. The membrane proteins are the rocks and islands in the ocean. Labelling the membrane protein target with a DNA tag is like having a lighthouse on the target protein to direct the specific screening of DNA-encoded chemical libraries for drug discovery. Credit: The University of Hong Kong

Background
Membrane proteins on the cell surface perform a myriad of biological functions that are vital to the survival of cells and organisms. Not surprisingly, numerous human diseases are associated with aberrant membrane protein functions. Indeed, membrane proteins account for over 60% of the targets of all FDA-approved small-molecule drugs. The G-protein coupled receptor (GPCR) superfamily alone, as the largest class of cell-surface receptors, are the targets of ~34% of all clinical drugs. However, despite the significance, drug discovery against membrane proteins is notoriously challenging, mainly due to the special property of their natural habitat: the cell membrane. Moreover, membrane proteins are also difficult to study in an isolated form, as they tend to lose essential cellular feature and may be deactivated. In fact, membrane proteins have long been considered as a type of “undruggable” targets in the pharmaceutical industry.


In recent years, DNA-encoded chemical library (DEL) has emerged and become a powerful drug screening technology. To simplify, we can use a book library as an example. In a library, each book is indexed with a catalog number and spatially encoded with a specific location on a bookshelf. Analogously, in a DEL, each chemical compound is attached with a unique DNA tag, which serves as the “catalog number” recording the structural information of the compound. With DNA encoding, all library compounds can be mixed and screened against the target simultaneously to discover the ones that can modulate the biological functions of the target, e.g. inhibiting the proteins that are aberrantly active in malignant cancers. DELs can contain astonishingly large numbers of test compounds (billions or even trillions), and DEL screening can be conducted in just a few hours in a regular chemistry lab. Today, DEL has been widely adopted by nearly all major pharmaceutical industry worldwide. However, DEL also had encountered significant difficulties in interrogating membrane proteins on live cells.

2 Key findings: Tracking and Boosting
There are two hurdles that the team has overcome to enable the application of DEL on live cells. First, cell surface is not a smooth convex shape like a balloon; it is extremely complex with hundreds of different biomolecules with a rugged topology; thus, locating the desired target on the cells surface is like finding a single tree in a thick tropical forest. The team has overcome this “target specificity” problem by using a method they previously developed: DNA-programmed affinity labeling (DPAL). This method utilizes a DNA-based probe system that can specifically deliver a DNA tag to the desired protein on live cells, and the DNA tag serves as a beacon to direct target-specific DEL screening. In other words, the team first installed a “tracker” on the target to achieve screening specificity.

The second challenge is target abundance. Typically, membrane proteins exist in nanomolar to low micromolar concentration, which is far below the high micromolar concentration needed to capture the tiny fraction of binders among billions of non-binders in a library. To solve this problem, the team employed a novel strategy by using complementary sequences in the DNA tag on the target protein and the actual library, so that the library can hybridize close to the target, thereby “boosting” the effective concentration of the target protein. In other words, the “tracker” can not only help the library locate the target, but also create an attractive force to concentrate the library around the target, not being distracted by the non-binding population.

In the publication, the team reports their detailed methodology development, and they also demonstrate the generality and performance of this method by screening a 30.42-million-compound library against folate receptor (FR), carbonic anhydrase 12 (CA-12), and epidermal growth factor receptor (EGFR) on live cells, all are important targets in anti-cancer drug discovery. This approach is expected to broadly applicable to many membrane proteins. For example, classical drug targets, such as GPCRs and ion channels, may be revisited in a live cell setting to identify new drug discovery opportunities by harnessing the power of DEL.

“We expect to the utility of this method is not limited to drug discovery, but also in academic research to explore challenging biological systems, such as oligomeric membrane protein complexes and cell-cell communications,” said Dr. Xiaoyu Li.

Co-corresponding author Professor Yizhou Li from Chongqing University said: “This method has the potential to facilitate drug discovery for membrane proteins with the power of large and complex chemical diversity from DNA-encoded chemical libraries.” Co-corresponding author Professor Yan Cao from Second Military Medical University in Shanghai added: “This technology is an effective tool for characterizing ligand-target interaction; it will cast new light on the development of high throughput screening methods, and thus facilitate the fishing of ligands targeting membrane proteins.”

Reference: “Selection of DNA-encoded chemical libraries against endogenous membrane proteins on live cells” by Yiran Huang, Ling Meng, Qigui Nie, Yu Zhou, Langdong Chen, Shilian Yang, Yi Man Eva Fung, Xiaomeng Li, Cen Huang, Yan Cao, Yizhou Li and Xiaoyu Li, 21 December 2020, Nature Chemistry.
DOI: 10.1038/s41557-020-00605-x

About the research team
The research was conducted by a team led by Dr. Xiaoyu Li from Research Division for Chemistry. Postdoctoral fellow Dr. Yiran Huang from Dr. Li’s group is the first author. Professor Yizhou Li from School of Pharmaceutical Sciences, Chongqing University and Professor Yan Cao from School of Pharmacy, Second Military Medical University in Shanghai are co-corresponding authors. Other HKU scientists in the Research Division for Chemistry contributing to the research include Miss Ling MENG, PhD student; Dr. Yu ZHOU, postdoctoral fellow; Dr. Yi Man Eva FUNG, Research Officer; Dr. Xiaomeng LI, postdoctoral fellow; and Mr. Cen HUANG, PhD student.

This work was supported by Research Grants Council of Hong Kong, Laboratory for Synthetic Chemistry and Chemical Biology of Health@InnoHK of Innovation and Technology Commission of Hong Kong, National Natural Science Foundation of China, and State Key Laboratory of Synthetic Chemistry at The University of Hong Kong. We thank the Centre for PanorOmic Sciences (CPOS) Genomics Core at HKU for analysis support.

About Dr Xiaoyu Li
Dr Xiaoyu Li is an Associate Professor of Research Division for Chemistry at The University of Hong Kong. His research interests lie in the fields of Chemical Biology, focusing on the development of new methods and enabling tools for both basic research and drug discovery. His research activities have been focusing on three areas: DNA-encoded chemical library (DEL) and its applications, protein labeling and profiling, and target identification and mechanism study of bioactive compounds.

 

[thegreenhand]

Just read the article fully - that DEL shit sounds cool af

Perhaps I’m misunderstanding the definition of “membrane protein” but wouldn’t any post synaptic receptor agonist fit this description? Like LSD and 5HT2a, for example

 

[thegreenhand]

on the bright side, 2020 has brought us significant mRNA research at rapid pace

 

[Skorpio]

In fact, membrane proteins have long been considered as a type of “undruggable” targets in the pharmaceutical industry.

I'm pretty sure this statement is bullshit. Plenty of drugs target membrane proteins, like maybe even a majority of them.

 

[thegreenhand]

I'm pretty sure this statement is bullshit. Plenty of drugs target membrane proteins, like maybe even a majority of them.

Yeah I have trouble believing that too. Hence, why I asked about LSD. I had to make sure my entire conception of pharmacology wasn’t wrong lmao

 

[Nagelfar]

I'm pretty sure this statement is bullshit. Plenty of drugs target membrane proteins, like maybe even a majority of them.

It clearly states as much, it's talking about previously unassailable ones:

Indeed, membrane proteins account for over 60% of the targets of all FDA-approved small-molecule drugs.

 

[thegreenhand]

It clearly states as much, it's talking about previously unassailable ones:

Yep definitely missed that line, my bad

 

[Skorpio]

It clearly states as much, it's talking about previously unassailable ones:

Then where is the proof of concept of targeting a receptor that has evaded ligand design previously? Folate receptor, carbonic anhydrase, and epidermal growth factor receptor have ligands, do they not?

 

[Nagelfar]

Moreover, membrane proteins are also difficult to study in an isolated form, as they tend to lose essential cellular feature and may be deactivated.

↑in search for new novel ligands for drugs, a lot of in vitro techniques have to be used to isolate: this appears to allow tagging for improved in vivo study or to locate where the site of a receptor is that evades in vitro conditions by becoming inactive during that process.

Any drug whatsoever that has had a hurdle in it's development due to reasons of isolating the target for study when scrutinized fall under this criteria.

 

[S.J.B.]

4-Aryl-1-oxa-4,9-diazaspiro[5.5]undecane Derivatives as Dual μ-Opioid Receptor Agonists and σ1 Receptor Antagonists for the Treatment of Pain
Corresponding author: Carmen Almansa (Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals SA, Barcelona, Spain)
Journal of Medicinal Chemistry 2020, Volume 63, Issue 5, Pages 2434–2454
Published online November 19th, 2019
https://doi.org/10.1021/acs.jmedchem.9b01256

The synthesis and pharmacological activity of a new series of 1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the sigma-1 receptor (σ1R) and the μ-opioid receptor (MOR) are reported. The different positions of the central scaffold, designed using a merging strategy of both target pharmacophores, were explored using a versatile synthetic approach. Phenethyl derivatives in position 9, substituted pyridyl moieties in position 4 and small alkyl groups in position 2 provided the best profiles. One of the best compounds, 15au, showed a balanced dual profile (i.e., MOR agonism and sigma antagonism) and a potent analgesic activity, comparable to the MOR agonist oxycodone in the paw pressure test in mice. Contrary to oxycodone, as expected from the addition of σ1R antagonism, 15au showed local, peripheral activity in this test, which was reversed by the σ1R agonist PRE-084. At equianalgesic doses, 15au showed less constipation than oxycodone, providing evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics.

 

[S.J.B.]

Discovery of EST73502, a Dual μ-Opioid Receptor Agonist and σ1 Receptor Antagonist Clinical Candidate for the Treatment of Pain
Corresponding author: Carmen Almansa (ESTEVE Pharmaceuticals S.A., Barcelona, Spain)
Journal of Medicinal Chemistry 2020, Volume 63, Issue 24, Pages 15508–15526
Published online October 16th, 2020
https://doi.org/10.1021/acs.jmedchem.0c01127

The synthesis and pharmacological activity of a new series of 4-alkyl-1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the σ1 receptor (σ1R) and the μ-opioid receptor (MOR) are reported. A lead optimization program over the initial 4-aryl analogues provided 4-alkyl derivatives with the desired functionality and good selectivity and ADME profiles. Compound 14u (EST73502) showed MOR agonism and σ1R antagonism and a potent analgesic activity, comparable to the MOR agonist oxycodone in animal models of acute and chronic pain after single and repeated administration. Contrary to oxycodone, 14u produces analgesic activity with reduced opioid-induced relevant adverse events, like intestinal transit inhibition and naloxone-precipitated behavioral signs of opiate withdrawal. These results provide evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics and were the basis for the selection of 14u as a clinical candidate for the treatment of pain.