Characterization of a Nonselective Opioid Receptor Functional Antagonist: Implications for Development as a Novel Opioid Dependence Medication DOI Open Access

Siavash Shahbazi Nia,

Yuma T. Ortiz, Julio D. Zuarth Gonzalez

et al.

ACS Pharmacology & Translational Science, Journal Year: 2024, Volume and Issue: 7(3), P. 654 - 666

Published: Feb. 12, 2024

Opioids represent the most extensive category of abused substances in United States, and number fatalities caused by these drugs exceeds those associated with all other drug overdoses combined. The administration naltrexone, a potent pan-opioid receptor antagonist, to an individual dependent on opioids can trigger opioid withdrawal induce severe side effects. There is pressing demand for antagonists free In our laboratory, we have identified compound affinity mu, delta, kappa receptors range 150–250 nM. This blood–brain barrier (BBB)-permeant was metabolically stable vitro vivo. Our vivo work demonstrated that 1–10 mg/kg intraperitoneal produces moderate efficacy antagonizing morphine-induced antiallodynia effects chemotherapy-induced peripheral neuropathy (CIPN) model. treatment well-tolerated did not cause behavioral changes. We observed fast elimination rate this molecule. Furthermore, no organ toxicity during chronic over 14-day period. Overall, report novel functional antagonist holds promise developing therapeutic.

Language: Английский

Permeability of Metformin across an In Vitro Blood–Brain Barrier Model during Normoxia and Oxygen-Glucose Deprivation Conditions: Role of Organic Cation Transporters (Octs) DOI Creative Commons
Sejal Sharma, Yong Zhang,

Khondker Ayesha Akter

et al.

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(5), P. 1357 - 1357

Published: April 28, 2023

Our lab previously established that metformin, a first-line type two diabetes treatment, activates the Nrf2 pathway and improves post-stroke recovery. Metformin’s brain permeability value potential interaction with blood–brain barrier (BBB) uptake efflux transporters are currently unknown. Metformin has been shown to be substrate of organic cationic (Octs) in liver kidneys. Brain endothelial cells at BBB have express Octs; thus, we hypothesize metformin uses Octs for its transport across BBB. We used co-culture model primary astrocytes as an vitro conduct studies during normoxia hypoxia using oxygen–glucose deprivation (OGD) conditions. was quantified highly sensitive LC-MS/MS method. further checked protein expression Western blot analysis. Lastly, completed plasma glycoprotein (P-GP) assay. results showed is permeable molecule, Oct1 transport, does not interact P-GP. During OGD, found alterations increased metformin. Additionally, selective key determinant metformin’s providing novel target improving ischemic drug delivery.

Language: Английский

Citations

31
Mucoadhesive chitosan-poly (lactic-co-glycolic acid) nanoparticles for intranasal delivery of quetiapine – Development & characterization in physiologically relevant 3D tissue models DOI
Dnyandev Gadhave, Mural Quadros,

Akanksha Ravindra Ugale

et al.

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 267, P. 131491 - 131491

Published: April 9, 2024

Language: Английский

Citations

4
The evolution of small molecule enzyme activators DOI
Louise F. Dow,

Alfie M. Case,

Megan P. Paustian

et al.

RSC Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 14(11), P. 2206 - 2230

Published: Jan. 1, 2023

There is a myriad of enzymes within the body responsible for maintaining homeostasis by providing means to convert substrates products as and when required. Physiological are tightly controlled many signaling pathways their subsequently control other pathways. Traditionally, most drug discovery efforts focus on identifying enzyme inhibitors, due upregulation being prevalent in diseases existence endogenous that can be modified afford inhibitor compounds. As downregulation reduction activators observed multiple diseases, identification small molecules with ability activate has recently entered medicinal chemistry toolbox chemical probes potential therapeutics an alternative intervene diseases. In this review we highlight progress made advancement non-kinase treating various disease states.

Language: Английский

Citations

10
Evaluation of Systemic and Brain Pharmacokinetic Parameters for Repurposing Metformin Using Intravenous Bolus Administration DOI Open Access
Sejal Sharma, Yong Zhang, Dhaval Patel

et al.

Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2024, Volume and Issue: 392(1), P. 100013 - 100013

Published: May 22, 2024

Metformin's potential in treating ischemic stroke and neurodegenerative conditions is of growing interest. Yet, the absence established systemic brain pharmacokinetic (PK) parameters at relevant preclinical doses presents a significant knowledge gap. This study highlights these PK importance using pharmacologically to pharmacodynamics related diseases. A liquid chromatography with tandem mass spectrometry method measure metformin levels plasma, brain, cerebrospinal fluid was developed validated. In vitro assays examined tissue binding metabolic stability. Intravenous bolus administration C57BL6 mice covered low- high-dose range maintaining pharmacological relevance. Quantification used assess parameters, such as unidirectional blood-to-brain constant (Kin) unbound brain-to-plasma ratio (Kp, uu, brain). Metformin exhibited no mouse plasma remained metabolically stable. It rapidly entered reaching detectable little 5 minutes. Kin value 1.87 ± 0.27 μL/g/min obtained. As dose increased, Kp, showed decreased value, implying saturation, but this did not affect an increase absolute concentrations. quantifiable 30 minutes over time, concentrations lower than those across all doses. Our findings emphasize selection based on for studies. We anticipate further investigations focusing PKs disease conditions, stroke. SIGNIFICANCE STATEMENT: The establishes crucial diseases, addressing emphasizes selecting highlight metformin's rapid entry, minimal binding, necessity considering studies provides foundation future into efficacy disease(s).

Language: Английский

Citations

3
Imidazole Bioisostere Activators of Endopeptidase Neurolysin with Enhanced Potency and Metabolic Stability DOI
Md. Shafikur Rahman,

Shiva Hadi Esfahani,

Yong Zhang

et al.

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(4), P. 510 - 517

Published: March 29, 2024

The peptidase neurolysin (Nln) has been validated as a potential target for developing therapeutics ischemic stroke (IS). Overexpression of Nln in mouse model IS provides significant cerebroprotection, leading to reduced infarction size and edema volume. Pharmacological inhibition the post-stroke brain worsens neurological outcomes. A virtual screen identified dipeptide small-molecule activators Nln. Optimization studies resulted class peptidomimetic compounds with promising activity. However, these still possessed an amide bond that compromised their stability plasma brain. Herein, we report synthesis characterization series bioisosteres based on our leads. Imidazole-based afford scaffolds increased potency activate combined enhanced significantly better permeability over original hits.

Language: Английский

Citations

1
Discovery of the Next Generation of Non-peptidomimetic Neurolysin Activators with High Blood-Brain Barrier Permeability: a Pharmacokinetics Study in Healthy and Stroke Animals DOI
Yong Zhang, Sejal Sharma, Shirisha Jonnalagadda

et al.

Pharmaceutical Research, Journal Year: 2023, Volume and Issue: 40(11), P. 2747 - 2758

Published: Oct. 13, 2023

Language: Английский

Citations

3
Small molecule neurolysin activators, potential multi-mechanism agents for ischemic stroke therapy DOI Open Access

Shiva Hadi Esfahani,

Thomas J. Abbruscato, Paul C. Trippier

et al.

Expert Opinion on Therapeutic Targets, Journal Year: 2022, Volume and Issue: 26(5), P. 401 - 404

Published: May 4, 2022

KEYWORDS: allosteric enhancerallosteric activatordrug-discoverycerebroprotective therapymulti-targetstroke neuroprotectionenzyme activatorpeptidase activator

Language: Английский

Citations

5
Systemic and Brain Pharmacokinetics of Milnacipran in Mice: Comparison of Intraperitoneal and Intravenous Administration DOI Creative Commons
Sounak Bagchi,

Ehsan Nozohouri,

Yeseul Ahn

et al.

Pharmaceutics, Journal Year: 2023, Volume and Issue: 16(1), P. 53 - 53

Published: Dec. 29, 2023

Milnacipran is a dual serotonin and norepinephrine reuptake inhibitor, clinically used for the treatment of major depression or fibromyalgia. Currently, there are no studies reporting pharmacokinetics (PK) milnacipran after intraperitoneal (IP) injection, despite this being primary administration route in numerous experimental using drug. Therefore, present study was designed to investigate PK profile IP-administered mice compare it intravenous (IV) route. First liquid chromatography–mass spectrometry (LC-MS/MS) method developed validated accurately quantify biological samples. The blood brain samples collected at various time-points post-administration. Non-compartmental analyses were employed determine key parameters. maximum concentration (Cmax) drug plasma 5 min IP administration, whereas brain, 60 both routes administration. Curiously, majority parameters similar irrespective route, bioavailability 92.5% injection. These findings provide insight into milnacipran’s absorption, distribution, elimination characteristics first time should be valuable future pharmacological studies.

Language: Английский

Citations

2
Characterization of a Nonselective Opioid Receptor Functional Antagonist: Implications for Development as a Novel Opioid Dependence Medication DOI Open Access

Siavash Shahbazi Nia,

Yuma T. Ortiz, Julio D. Zuarth Gonzalez

et al.

ACS Pharmacology & Translational Science, Journal Year: 2024, Volume and Issue: 7(3), P. 654 - 666

Published: Feb. 12, 2024

Opioids represent the most extensive category of abused substances in United States, and number fatalities caused by these drugs exceeds those associated with all other drug overdoses combined. The administration naltrexone, a potent pan-opioid receptor antagonist, to an individual dependent on opioids can trigger opioid withdrawal induce severe side effects. There is pressing demand for antagonists free In our laboratory, we have identified compound affinity mu, delta, kappa receptors range 150–250 nM. This blood–brain barrier (BBB)-permeant was metabolically stable vitro vivo. Our vivo work demonstrated that 1–10 mg/kg intraperitoneal produces moderate efficacy antagonizing morphine-induced antiallodynia effects chemotherapy-induced peripheral neuropathy (CIPN) model. treatment well-tolerated did not cause behavioral changes. We observed fast elimination rate this molecule. Furthermore, no organ toxicity during chronic over 14-day period. Overall, report novel functional antagonist holds promise developing therapeutic.

Language: Английский

Citations

0