The Synthesis of NPFF Receptor Ligand

A dual-acting compound with opioid agonist & neuropeptide FF

antagonist

Introduction

Caroline Morris

Hernando, MSUniversity of Mississippi

Undergraduate JuniorB.S in Pharmaceutical Sciences,

pursuing Pharm.D

Table of Contents1. Background

2. Projected Solution

3. Methodology

4. Conclusion

5. Personal Development

6. Acknowledgements

7. Questions

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

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

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

Projected Solution

1. VBJ192 works- warm-water immersion test

Projected Solution

2. Blood-Brain Barrier

3. Structure-Activity Relationship (SAR)

Projected Solution

• Amidine functional groupcan penetrate the blood-brain barrier

• Similarities to VBJ192

Methodology

1. Synthesis of Benzyltriphenylphosphonium salt

A: 1 mole, B: 1 mole, C: 97% yield

A B C

Methodology

2. Wittig Reaction

A B

A: 34.62mmol, LDA: 38.06mmol, 1-benzylpiperidin-4-one: 6.7mL, B: 42.2% yield

Methodology

3. Bromination

A B

A: 5.58mmol, Br2: 8.37mmol, NaOH: 21.63mmol, B: 80.7% yield

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

Methodology

5. Garigipati Reaction



A B

A: 0.275mmol, NH4Cl: 0.495mmol, Al(CH3)3: 0.458mmol, B: 56% yield

Methodology

1. Filtration 2. Column Chromatography

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

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

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.

Methodology

-Bromination was successful! -Suzuki was successful!

Mass Spectrometry (MS)-verifies the mass of the compound

Conclusion

• We successfully modified VBJ192 into an amidine derivative• NMR verified

• Pharmacological evaluation will be performed on this compound

Personal Development

1. Honed research/lab skills2. Delved into Medicinal Chemistry3. Application of prior information4. Patience

Acknowledgements

Dr. Christopher McCurdyDr. Coco Kapanda

Kelsey LueckeDr. Velvet JourniganDr. Stephen Cutler

COBRE Grant P20GM104932

Questions

Wittig Mechanism

Bromination

Suzuki

Garigipati