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![Page 1: Powerpoint Presentation](https://reader035.fdocumento.com/reader035/viewer/2022070514/587ccb5b1a28abfa018b6239/html5/thumbnails/1.jpg)
The Synthesis of NPFF Receptor Ligand
A dual-acting compound with opioid agonist & neuropeptide FF
antagonist
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Introduction
Caroline Morris
Hernando, MSUniversity of Mississippi
Undergraduate JuniorB.S in Pharmaceutical Sciences,
pursuing Pharm.D
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Table of Contents1. Background
2. Projected Solution
3. Methodology
4. Conclusion
5. Personal Development
6. Acknowledgements
7. Questions
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Background
• Chronic pain affects 116 million Americans per year 1
• Opioid drugs are the primary prescribed pain-killers
1O’Reilly, Kevin B. American Medical News. 2011
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Background
• Opioid drugs have several side effects:- digestive problems2
- addiction3
- tolerance3
As the dosage increases, the side effects increase until the point that the side effects outweigh the benefits
2Chan, Lingtak-Neander. Nutrition Issues in Gastroenterology. 20083Stuckert, Jeffery. Psych Central. 2011
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Projected Solution
• Previous research has discovered that the Neuropeptide FF antagonist receptors can prevent morphine-induced tolerance
• The use of a dual-acting compound with Opioid & NPFF receptors looks promising:
-opioid drug use without tolerance
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Projected Solution
1. VBJ192 works- warm-water immersion test
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Projected Solution
2. Blood-Brain Barrier
3. Structure-Activity Relationship (SAR)
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Projected Solution
• Amidine functional groupcan penetrate the blood-brain barrier
• Similarities to VBJ192
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Methodology
1. Synthesis of Benzyltriphenylphosphonium salt
A: 1 mole, B: 1 mole, C: 97% yield
A B C
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Methodology
2. Wittig Reaction
A B
A: 34.62mmol, LDA: 38.06mmol, 1-benzylpiperidin-4-one: 6.7mL, B: 42.2% yield
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Methodology
3. Bromination
A B
A: 5.58mmol, Br2: 8.37mmol, NaOH: 21.63mmol, B: 80.7% yield
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Methodology
4. Suzuki Coupling
A B C
A: 5.23mmol, B: 6.28mmol, Pd(PPh3)4: 0.1205g, K2CO3: 13.09mmol, C: 52.1% yield
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Methodology
5. Garigipati Reaction

A B
A: 0.275mmol, NH4Cl: 0.495mmol, Al(CH3)3: 0.458mmol, B: 56% yield
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Methodology
1. Filtration 2. Column Chromatography
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Methodology
• Because this synthesis required multiple steps, after each step, verification had to take place in before starting the next reaction
-in order to determine it was actually the desired product-make sure there were no impurities
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Methodology
Thin Layer Chromatography (TLC)- used to determine Rf value
Rf value = distance product traveled distance solvent traveled = 6.25 cm
8.00 cm = 0.781
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Methodology
TLC is also used to make comparisons:-the compound is the same across, verifying that the different tubes from column chromatography contain the same compound.
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Methodology
-Bromination was successful! -Suzuki was successful!
Mass Spectrometry (MS)-verifies the mass of the compound
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Conclusion
• We successfully modified VBJ192 into an amidine derivative• NMR verified
• Pharmacological evaluation will be performed on this compound
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Personal Development
1. Honed research/lab skills2. Delved into Medicinal Chemistry3. Application of prior information4. Patience
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Acknowledgements
Dr. Christopher McCurdyDr. Coco Kapanda
Kelsey LueckeDr. Velvet JourniganDr. Stephen Cutler
COBRE Grant P20GM104932
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Questions
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Wittig Mechanism
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Bromination
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Suzuki
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Garigipati