Researchers at Texas Tech are developing a new class of non-opioid compounds that target a key protein involved in chronic neuropathic pain. Backed by a $1.94 million NIH grant, their work could lead to safer, more effective treatments that avoid the risks of addiction and resistance tied to current medications.
Ahmed receives NIH grant to
investigate inhibitors targeting peripheral neuropathic pain.
Chronic pain is a widespread and debilitating
condition that often prompts healthcare providers to prescribe increasingly
higher doses of opioids. This reliance on opioids has contributed to a national
crisis, with more than 107,000 Americans dying from opioid-related overdoses
between December 2020 and December 2021, according to the American Medical
Association. In light of this public health emergency, there is a pressing need
to develop new therapies that are both effective and non-addictive.
To support progress in this area, the National
Institute of Neurological Disorders and Stroke at the National Institutes of Health has
awarded a five-year, $1.94 million grant titled “Identification of novel lead
EphB1/2 tyrosine kinase inhibitors targeting peripheral neuropathic pain” to
Mahmoud Salama Ahmed, Ph.D., a faculty member in the Department of
Pharmaceutical Sciences at the Texas Tech University Health Sciences Center
(TTUHSC) Jerry H. Hodge School of Pharmacy. The research team also includes
TTUHSC colleagues Jenny Wilkerson, Ph.D. (co-investigator), Heba Ewida, Ph.D.,
and graduate student Harrison Benson.
Early findings
on tetracycline combinations
In previous behavioral research studies, Ahmed’s
laboratory demonstrated significant reversal of thermal hyperalgesia
(heightened sensitivity to heat or thermal stimuli) and mechanical allodynia
(pain from a light touch, pressure, or movement) induced by experimental nerve
damage and a sciatic nerve constriction injury.
Ahmed’s previous research also revealed the synergism
of three tetracycline family members: minocycline, chlortetracycline, and
demeclocycline.
“That study showed the competitive inhibitory profile
of chlortetracycline and the catalytic binding domain of EphB1 tyrosine kinase
(transmembrane proteins that mediate communication between cells),” Ahmed
explained. “It also showed that the tetracycline combination reversed thermal
hyperalgesia and mechanical allodynia in various pain models. However, the IC50
(the amount of a drug needed to inhibit a biological process by 50%) for this
approach is in the low micromolar range, requiring a near-maximal dose of all
three antibiotics in combination.”
A micromolar is one-millionth (10^-6) of a mole, which
is a unit of measurement representing a specific number of molecules or atoms.
For some drugs, concentrations this high in humans are difficult to achieve without
producing unwanted side effects.
Limitations of
antibiotic-based approaches
While working at UT-Southwestern, Ahmed published a
paper at the proceedings of the National Academy of Sciences resolving the
crystal structure of one of the tetracyclines with the EphB1 tyrosine kinase
domain. Ahmed said this kinase is integrated into the progression of peripheral
neuropathic pain.
“However, it
doesn’t make sense that when we have a patient that’s suffering from a
peripheral neuropathic pain, we will give them this combo of the
tetracyclines,” Ahmed said. “Because in the long-term, some of the adverse
effects the patient might develop include antibiotic resistance. Also, the
binding of the tetracyclines to the kinase domain was not optimum. Based on
that, I started to look at the structure again, and I came up with new
structures to achieve more potency and selectivity.”
Collaboration
and compound development at ttu
Ahmed then began collaborating with Wilkerson at
TTUHSC. First, Ahmed’s lab conducted the design phase, synthesized (collected)
other evidence and findings from past research and conducted biochemical
validation. When the project was set to scale up and conduct in vivo,
pre-clinical models, they turned to Wilkerson’s lab.
Wilkerson has 17 years of experience researching the involvement of the immune system in various chronic neuropathic pain models. Using this expertise, Wilkerson’s laboratory will examine the potency of these new compounds to reverse or prevent behaviors associated with chronic neuropathic pain. Her laboratory will also determine if therapeutically relevant doses of these new compounds produce untoward behavioral side effects.
“This project holds a lot of promise because, for so
many people, opioids and gabapentinoids are the main options to treat chronic
pain, and we know that these drugs often do not work to adequately control
pain,” Wilkerson said. “Additionally, this project is very exciting because we
might be able to prevent chronic pain from developing.”
Preclinical
testing and therapeutic potential
As they prepare for this latest study, Ahmed said they
have 50 to 60 molecules in hand that exhibit better activity when compared to
the tetracyclines used to target the EphB1 tyrosine kinase domain. Two of these
molecules are undergoing preclinical evaluation for reversing all the key
parameters for peripheral neuropathic pain, such as thermal hyperalgesia and
mechanical allodynia.
“The EphB1/2 tyrosine kinase domain inhibitors have
the potential to reverse the thermal hyperalgesia and the mechanical allodynia,
and those stimuli are interrelated to peripheral neuropathic pain,” Ahmed said.
“Our overall goal is to pharmacologically examine whether selective EphB1/2
tyrosine kinase inhibition is necessary and sufficient to reverse and/or block
peripheral neuropathic pain development.”
The
Ahmed-Wilkerson team hypothesizes that their novel small molecules, which are
not related to the tetracycline scaffold, will inhibit EphB1/2 tyrosine kinase
signaling.
“These small molecules could prove to be novel tools
to investigate the mechanisms that either block or reverse peripheral and
central nervous system neuronal activation and nerve damage,” Ahmed said. “This
will lead to decreased neuropathic pain-related biomarkers and behaviors
associated with peripheral neuropathic pain.”
The research was funded by the National Institute of Neurological Disorders and Stroke.
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