This document summarizes the synthesis of a novel compound with potential use as a painkiller with reduced side effects. The compound is a dual-acting ligand for opioid and neuropeptide FF receptors. It was synthesized in 5 steps: 1) a Wittig reaction, 2) bromination, 3) Suzuki coupling, 4) Garigipati reaction, and 5) purification via filtration and chromatography. Characterization using NMR and mass spectrometry confirmed the successful modification of an existing compound, VBJ192, into an amidine derivative for further pharmacological evaluation and testing as a painkiller with fewer side effects than traditional opioids.
This document appears to be a 10 page exam for pharmacology and dental materia medica consisting of 43 multiple choice questions. The questions cover topics such as general pharmacology, the autonomic nervous system, sedative-hypnotics, analgesics, local anesthetics, antimicrobial agents, and dental antiseptics. Each question is followed by 5 possible answers with the key/correct answer indicated at the end. The questions probe students' knowledge of medication mechanisms of action, side effects, treatment choices for various medical conditions, and more.
This document contains a collection of questions from various ANZCA exams on the topics of pharmacology and general anaesthetics. The questions cover topics such as pharmacokinetics, drug properties, mechanisms of action, volatile anaesthetic agents, and minimum alveolar concentration. The questions are multiple choice format and cover basic concepts as well as specific drug properties.
This document summarizes a presentation on medication-assisted treatment for opioid addiction. It discusses the history of treatment approaches, including the development of methadone and buprenorphine maintenance therapies. Studies show that agonist therapies like methadone and buprenorphine are more effective at retaining patients in treatment and reducing illicit opioid use than non-medication approaches. While both methadone and buprenorphine are effective, buprenorphine has a safer side effect profile but its effectiveness may be limited by lower monitoring and adherence compared to methadone treatment. The document reviews several studies demonstrating the benefits of long-term agonist therapy over detoxification or short-term medication approaches for opioid
This document summarizes a CDC training on using digital and social media to address the opioid epidemic. It includes:
- Presenters from the CDC's National Center for Injury Prevention and Control who will discuss communication principles, planning tactics, and using social media best practices.
- Learning objectives around explaining the value of communication, demonstrating social media processes, identifying best practices, and preparing to use social media to impact the opioid problem.
- An agenda that covers surveys, introductions, an opioid epidemic overview, health communication basics, social media basics and best practices, and exercises.
This document discusses a presentation on expanding the use of naloxone. The presentation includes three speakers who will discuss (1) naloxone collaborative practice agreements with pharmacies, (2) a model for using intranasal naloxone as a universal precaution for patients on chronic opioid therapy, and (3) whether co-prescribing intranasal naloxone impacts overdose deaths. The document provides background on the speakers and moderators, as well as learning objectives and an agenda for the presentation.
The document discusses opioid analgesics and their mechanisms of action. It describes the different opioid receptor subtypes and endogenous opioid peptides. It then discusses various exogenous opioid agonists and antagonists, their potencies, durations of action, and metabolic pathways. Adverse effects and issues of tolerance and dependence are also summarized.
The Empower Veterans Program provides intensive, integrated self-care coaching through group and individual sessions for veterans suffering from chronic pain. Over 10 weeks, veterans receive training in whole health and well-being, acceptance and commitment therapy, and mindful movement. Preliminary results show improvements in pain, functioning, mental health, and quality of life for veterans, as well as decreased healthcare utilization and costs. The program aims to safely empower veterans with chronic pain through a multidisciplinary approach that promotes self-management over passive treatments.
This document provides an overview of basic neurochemistry. It discusses the organization of the nervous system including the central nervous system made up of the brain and spinal cord, and the peripheral nervous system. It describes the basic neuron structure and function including dendrites, axons, myelin sheaths, and synapses. It explains action potentials and neurotransmission involving neurotransmitters such as serotonin, dopamine, GABA, and acetylcholine. It also summarizes receptors, fate of neurotransmitters, and factors involved in neuropharmacology.
This document appears to be a 10 page exam for pharmacology and dental materia medica consisting of 43 multiple choice questions. The questions cover topics such as general pharmacology, the autonomic nervous system, sedative-hypnotics, analgesics, local anesthetics, antimicrobial agents, and dental antiseptics. Each question is followed by 5 possible answers with the key/correct answer indicated at the end. The questions probe students' knowledge of medication mechanisms of action, side effects, treatment choices for various medical conditions, and more.
This document contains a collection of questions from various ANZCA exams on the topics of pharmacology and general anaesthetics. The questions cover topics such as pharmacokinetics, drug properties, mechanisms of action, volatile anaesthetic agents, and minimum alveolar concentration. The questions are multiple choice format and cover basic concepts as well as specific drug properties.
This document summarizes a presentation on medication-assisted treatment for opioid addiction. It discusses the history of treatment approaches, including the development of methadone and buprenorphine maintenance therapies. Studies show that agonist therapies like methadone and buprenorphine are more effective at retaining patients in treatment and reducing illicit opioid use than non-medication approaches. While both methadone and buprenorphine are effective, buprenorphine has a safer side effect profile but its effectiveness may be limited by lower monitoring and adherence compared to methadone treatment. The document reviews several studies demonstrating the benefits of long-term agonist therapy over detoxification or short-term medication approaches for opioid
This document summarizes a CDC training on using digital and social media to address the opioid epidemic. It includes:
- Presenters from the CDC's National Center for Injury Prevention and Control who will discuss communication principles, planning tactics, and using social media best practices.
- Learning objectives around explaining the value of communication, demonstrating social media processes, identifying best practices, and preparing to use social media to impact the opioid problem.
- An agenda that covers surveys, introductions, an opioid epidemic overview, health communication basics, social media basics and best practices, and exercises.
This document discusses a presentation on expanding the use of naloxone. The presentation includes three speakers who will discuss (1) naloxone collaborative practice agreements with pharmacies, (2) a model for using intranasal naloxone as a universal precaution for patients on chronic opioid therapy, and (3) whether co-prescribing intranasal naloxone impacts overdose deaths. The document provides background on the speakers and moderators, as well as learning objectives and an agenda for the presentation.
The document discusses opioid analgesics and their mechanisms of action. It describes the different opioid receptor subtypes and endogenous opioid peptides. It then discusses various exogenous opioid agonists and antagonists, their potencies, durations of action, and metabolic pathways. Adverse effects and issues of tolerance and dependence are also summarized.
The Empower Veterans Program provides intensive, integrated self-care coaching through group and individual sessions for veterans suffering from chronic pain. Over 10 weeks, veterans receive training in whole health and well-being, acceptance and commitment therapy, and mindful movement. Preliminary results show improvements in pain, functioning, mental health, and quality of life for veterans, as well as decreased healthcare utilization and costs. The program aims to safely empower veterans with chronic pain through a multidisciplinary approach that promotes self-management over passive treatments.
This document provides an overview of basic neurochemistry. It discusses the organization of the nervous system including the central nervous system made up of the brain and spinal cord, and the peripheral nervous system. It describes the basic neuron structure and function including dendrites, axons, myelin sheaths, and synapses. It explains action potentials and neurotransmission involving neurotransmitters such as serotonin, dopamine, GABA, and acetylcholine. It also summarizes receptors, fate of neurotransmitters, and factors involved in neuropharmacology.
The document summarizes a lecture on drug design and discovery. It discusses:
1) Drug sources can come from animals, plants, inorganic substances, or be synthesized. Membrane proteins, DNA, RNA, and enzymes are common drug targets.
2) Computer-aided drug design techniques like ligand-based drug design using QSARs and pharmacophores, and structure-based drug design using docking can aid in drug discovery.
3) The drug discovery process involves identifying a disease target, finding a lead compound, optimizing the lead through chemical modifications, and conducting preclinical and clinical trials which can take 10-12 years.
This document describes the development and validation of an RP-HPLC method for the quantification of flunarizine dihydrochloride. Key steps included selecting the instrument and optimizing conditions such as the column, mobile phase, and detection wavelength. The method was then validated based on parameters like accuracy, precision, specificity, detection limit, quantitation limit, and linearity range according to ICH guidelines. The proposed RP-HPLC method was found to be simple, accurate, precise and cost-effective for the analysis of flunarizine dihydrochloride in drug substances and pharmaceutical formulations.
Residual solvents
USP <467>
ICH Q3C
Classification of Residual Solvents by Risk Assessment
Options for Determining Levels of Class 2 Residual Solvents
Methods For Establishing Exposure Limits
Analytical Procedures
The document summarizes research into synthesizing a highly potent and selective mu-opioid ligand. Key steps in the synthesis of compound 3 are described, which involves lithiation, dehydration, alkylation, bromination/reduction, etherification, deprotection, triflation, and Suzuki coupling. Compound 3 will be tested for in vitro activity and compared to an enantiopure version to gain insight into opioid receptor interactions that could aid future mu-opioid agonist design.
This document summarizes the results of analyzing the chemical composition of Gardasil 9 vaccine using mass spectrometry. Over 300 unknown signals were detected in the vaccine, with only 22% able to be potentially identified. While some expected viral proteins were found, many unknown compounds were present. Several of the unknown compounds were potentially toxic based on molecular weight matches to toxin databases. There are significant variations in contaminants and impurities between vaccine lots. Further targeted analysis is still needed to confirm the identity and toxicity of the unknown compounds detected.
This document describes an interlaboratory study conducted by 11 laboratories to evaluate the precision and practicality of a nonaqueous capillary electrophoresis (NACE) method for determining the content of R-timolol impurity in S-timolol maleate samples. The study was designed according to ISO guidelines and involved qualitative and quantitative assessments of the method performances within and between laboratories. Statistical analysis of the results allowed estimation of variances within and between laboratories, days, and replicates to determine the method's repeatability and reproducibility. The estimated measurement uncertainty was found to be concentration-dependent above a certain threshold.
Enzymes are common pharmaceutical targets as they catalyze important physiological processes. Measuring enzyme kinetics via the Michaelis-Menten equation requires rapidly mixing enzymes and substrates to measure initial reaction rates. Various detection methods exist, including spectrophotometry, fluorimetry, radioactivity, and coupled reactions. Stopped flow is often used to rapidly mix reactants for kinetic analysis. Careful assay design is needed for each specific enzyme reaction.
microspheres,types, advantages and disadvantages,methods of preparation, evaluation or characterization of microspheres and applications of microspheres in various pharmaceutical fields.
CBDV is a research venture seeking to develop analytical methods like HPLC to quantify psilocybin in psychedelic mushrooms for cultivation sites, as current methods take too long; they developed a 3.5 minute HPLC method using ammonium bicarbonate and acetonitrile to quantify psilocybin without degradation, and will next explore extraction methods from mushrooms.
Limit value for urinary 1-hydroxypyrene as marker of occupational exposure to...IndusTox Consult
1. The document proposes a biological occupational exposure limit (BOEL) for polycyclic aromatic hydrocarbons (PAH) of 1.0 μmol/mol creatinine for 1-hydroxypyrene in urine. This limit is based on the lowest observed level without genotoxic effects found in a meta-analysis of studies.
2. The limit accounts for different PAH profiles by adjusting the limit based on the pyrene to benzo(a)pyrene ratio, with a default ratio of 2.5 corresponding to the proposed limit of 1.0 μmol/mol creatinine.
3. While an occupational exposure limit of 200 ng/m3 for benzo(a)py
The document proposes updating the biological occupational exposure limit (BOEL) for polycyclic aromatic hydrocarbons (PAH) to 1-hydroxypyrene in urine. It conducted a literature review to identify the lowest level of 1-hydroxypyrene without genotoxic effects, finding a key study showing no increased risk below 1.0 μmol/mol. This level is proposed as the new BOEL. It also recommends adjusting the limit based on the pyrene/benzo(a)pyrene ratio of a worker's exposure. While not legally binding, the proposal aims to supplement an existing air concentration limit and support industry adoption of a health-based biological monitoring standard.
This document summarizes a student's research project on synthesizing modified substrates for a glycosyltransferase enzyme involved in mycobacterium tuberculosis cell wall biosynthesis. The student aimed to synthesize 4-deoxy-4-fluoro-α-D-glucopyranoside and 4-Deoxy-D-galactopyranose derivatives to study the enzyme's reaction mechanism. Several steps were taken to synthesize each compound, with improvements made when initial attempts failed or yields were low. Future work involves completing the syntheses, adding UDP groups, testing the modified substrates with the enzyme, and analyzing reaction intermediates to validate the proposed mechanism.
This document provides an overview of microdosing and phase 0 clinical trials. It defines microdosing as using extremely low, non-pharmacologically active doses of a drug to define its pharmacokinetic profile in humans. The goals of phase 0 trials are to provide early human PK and PD data prior to phase 1 testing in order to increase the chance of successful subsequent drug development. The document describes the design, procedures, analytical techniques like LC-MS and AMS, and regulatory guidelines for microdosing and phase 0 trials.
Formulation and evaluation of sustained release microspheres ofReshma Fathima .K
This document describes the formulation and evaluation of fenofibrate microspheres for sustained drug release. Fenofibrate microspheres were prepared using the emulsion-coacervation method with gelatin as the polymer. The microspheres were evaluated for particle size, drug entrapment efficiency, in vitro drug release, and stability. The results showed the microspheres had spherical morphology and successfully entrapped fenofibrate, providing sustained release over 12 hours. Thus, the fenofibrate microspheres developed in this study could be a promising approach for controlled delivery of this drug.
Comparative evaluation study on different brands of lisinopril tablet using h...Alexander Decker
The document summarizes a study that evaluated the chemical equivalence of nine different brands of lisinopril tablets using HPLC and UV spectrophotometry. The study found that only one brand passed tests using both methods, while five brands met limits for HPLC analysis. HPLC was determined to be a more suitable method for lisinopril assay given its sensitivity, reproducibility and accuracy compared to UV spectrophotometry.
This document discusses bioassays and techniques for measuring drug-target binding in drug development. It provides an overview of the multi-step drug development process and defines bioassays as assays involving biological samples that can be quantal or graded. It then describes various methods for measuring drug-target binding affinity, including radioligand binding assays, isothermal titration calorimetry, surface plasmon resonance, and microscale thermophoresis. These binding assays are important for both hit identification and lead optimization in drug development.
1) Computer-aided drug design (CADD) uses computational methods and resources to facilitate the design and discovery of new therapeutic solutions.
2) CADD can be used at various stages of drug discovery, including hit identification, hit-to-lead optimization, and lead optimization.
3) The objectives of CADD are to speed up the drug screening process and enable more rational and targeted drug design and testing.
The document summarizes a lecture on drug design and discovery. It discusses:
1) Drug sources can come from animals, plants, inorganic substances, or be synthesized. Membrane proteins, DNA, RNA, and enzymes are common drug targets.
2) Computer-aided drug design techniques like ligand-based drug design using QSARs and pharmacophores, and structure-based drug design using docking can aid in drug discovery.
3) The drug discovery process involves identifying a disease target, finding a lead compound, optimizing the lead through chemical modifications, and conducting preclinical and clinical trials which can take 10-12 years.
This document describes the development and validation of an RP-HPLC method for the quantification of flunarizine dihydrochloride. Key steps included selecting the instrument and optimizing conditions such as the column, mobile phase, and detection wavelength. The method was then validated based on parameters like accuracy, precision, specificity, detection limit, quantitation limit, and linearity range according to ICH guidelines. The proposed RP-HPLC method was found to be simple, accurate, precise and cost-effective for the analysis of flunarizine dihydrochloride in drug substances and pharmaceutical formulations.
Residual solvents
USP <467>
ICH Q3C
Classification of Residual Solvents by Risk Assessment
Options for Determining Levels of Class 2 Residual Solvents
Methods For Establishing Exposure Limits
Analytical Procedures
The document summarizes research into synthesizing a highly potent and selective mu-opioid ligand. Key steps in the synthesis of compound 3 are described, which involves lithiation, dehydration, alkylation, bromination/reduction, etherification, deprotection, triflation, and Suzuki coupling. Compound 3 will be tested for in vitro activity and compared to an enantiopure version to gain insight into opioid receptor interactions that could aid future mu-opioid agonist design.
This document summarizes the results of analyzing the chemical composition of Gardasil 9 vaccine using mass spectrometry. Over 300 unknown signals were detected in the vaccine, with only 22% able to be potentially identified. While some expected viral proteins were found, many unknown compounds were present. Several of the unknown compounds were potentially toxic based on molecular weight matches to toxin databases. There are significant variations in contaminants and impurities between vaccine lots. Further targeted analysis is still needed to confirm the identity and toxicity of the unknown compounds detected.
This document describes an interlaboratory study conducted by 11 laboratories to evaluate the precision and practicality of a nonaqueous capillary electrophoresis (NACE) method for determining the content of R-timolol impurity in S-timolol maleate samples. The study was designed according to ISO guidelines and involved qualitative and quantitative assessments of the method performances within and between laboratories. Statistical analysis of the results allowed estimation of variances within and between laboratories, days, and replicates to determine the method's repeatability and reproducibility. The estimated measurement uncertainty was found to be concentration-dependent above a certain threshold.
Enzymes are common pharmaceutical targets as they catalyze important physiological processes. Measuring enzyme kinetics via the Michaelis-Menten equation requires rapidly mixing enzymes and substrates to measure initial reaction rates. Various detection methods exist, including spectrophotometry, fluorimetry, radioactivity, and coupled reactions. Stopped flow is often used to rapidly mix reactants for kinetic analysis. Careful assay design is needed for each specific enzyme reaction.
microspheres,types, advantages and disadvantages,methods of preparation, evaluation or characterization of microspheres and applications of microspheres in various pharmaceutical fields.
CBDV is a research venture seeking to develop analytical methods like HPLC to quantify psilocybin in psychedelic mushrooms for cultivation sites, as current methods take too long; they developed a 3.5 minute HPLC method using ammonium bicarbonate and acetonitrile to quantify psilocybin without degradation, and will next explore extraction methods from mushrooms.
Limit value for urinary 1-hydroxypyrene as marker of occupational exposure to...IndusTox Consult
1. The document proposes a biological occupational exposure limit (BOEL) for polycyclic aromatic hydrocarbons (PAH) of 1.0 μmol/mol creatinine for 1-hydroxypyrene in urine. This limit is based on the lowest observed level without genotoxic effects found in a meta-analysis of studies.
2. The limit accounts for different PAH profiles by adjusting the limit based on the pyrene to benzo(a)pyrene ratio, with a default ratio of 2.5 corresponding to the proposed limit of 1.0 μmol/mol creatinine.
3. While an occupational exposure limit of 200 ng/m3 for benzo(a)py
The document proposes updating the biological occupational exposure limit (BOEL) for polycyclic aromatic hydrocarbons (PAH) to 1-hydroxypyrene in urine. It conducted a literature review to identify the lowest level of 1-hydroxypyrene without genotoxic effects, finding a key study showing no increased risk below 1.0 μmol/mol. This level is proposed as the new BOEL. It also recommends adjusting the limit based on the pyrene/benzo(a)pyrene ratio of a worker's exposure. While not legally binding, the proposal aims to supplement an existing air concentration limit and support industry adoption of a health-based biological monitoring standard.
This document summarizes a student's research project on synthesizing modified substrates for a glycosyltransferase enzyme involved in mycobacterium tuberculosis cell wall biosynthesis. The student aimed to synthesize 4-deoxy-4-fluoro-α-D-glucopyranoside and 4-Deoxy-D-galactopyranose derivatives to study the enzyme's reaction mechanism. Several steps were taken to synthesize each compound, with improvements made when initial attempts failed or yields were low. Future work involves completing the syntheses, adding UDP groups, testing the modified substrates with the enzyme, and analyzing reaction intermediates to validate the proposed mechanism.
This document provides an overview of microdosing and phase 0 clinical trials. It defines microdosing as using extremely low, non-pharmacologically active doses of a drug to define its pharmacokinetic profile in humans. The goals of phase 0 trials are to provide early human PK and PD data prior to phase 1 testing in order to increase the chance of successful subsequent drug development. The document describes the design, procedures, analytical techniques like LC-MS and AMS, and regulatory guidelines for microdosing and phase 0 trials.
Formulation and evaluation of sustained release microspheres ofReshma Fathima .K
This document describes the formulation and evaluation of fenofibrate microspheres for sustained drug release. Fenofibrate microspheres were prepared using the emulsion-coacervation method with gelatin as the polymer. The microspheres were evaluated for particle size, drug entrapment efficiency, in vitro drug release, and stability. The results showed the microspheres had spherical morphology and successfully entrapped fenofibrate, providing sustained release over 12 hours. Thus, the fenofibrate microspheres developed in this study could be a promising approach for controlled delivery of this drug.
Comparative evaluation study on different brands of lisinopril tablet using h...Alexander Decker
The document summarizes a study that evaluated the chemical equivalence of nine different brands of lisinopril tablets using HPLC and UV spectrophotometry. The study found that only one brand passed tests using both methods, while five brands met limits for HPLC analysis. HPLC was determined to be a more suitable method for lisinopril assay given its sensitivity, reproducibility and accuracy compared to UV spectrophotometry.
This document discusses bioassays and techniques for measuring drug-target binding in drug development. It provides an overview of the multi-step drug development process and defines bioassays as assays involving biological samples that can be quantal or graded. It then describes various methods for measuring drug-target binding affinity, including radioligand binding assays, isothermal titration calorimetry, surface plasmon resonance, and microscale thermophoresis. These binding assays are important for both hit identification and lead optimization in drug development.
1) Computer-aided drug design (CADD) uses computational methods and resources to facilitate the design and discovery of new therapeutic solutions.
2) CADD can be used at various stages of drug discovery, including hit identification, hit-to-lead optimization, and lead optimization.
3) The objectives of CADD are to speed up the drug screening process and enable more rational and targeted drug design and testing.
3. Table of Contents
1. Background
2. Projected Solution
3. Methodology
4. Conclusion
5. Personal Development
6. Acknowledgements
7. Questions
4. 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
5. 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. 2008
3Stuckert, Jeffery. Psych Central. 2011
6. 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
16. 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
17. 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
18. 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.
20. Conclusion
• We successfully modified VBJ192 into an amidine derivative
• NMR verified
• Pharmacological evaluation will be performed on this compound
21. Personal Development
1. Honed research/lab skills
2. Delved into Medicinal Chemistry
3. Application of prior information
4. Patience
http://www.amednews.com/article/20111017/profession/310179937/2/
http://www.iom.edu/activities/publichealth/painresearch/pain-care-improvements-recommended-in-iom-report.aspx
***So what’s the big deal? We have Americans in pain, and we have opioids to fight their pain…
2. http://www.medicine.virginia.edu/clinical/departments/medicine/divisions/digestive-health/nutrition-support-team/nutrition-articles/ChanArticle.pdf
--opioid receptors are also found in the gastrointestinal tract; causes issues with the normal motility and secretory functions within the tract
3. http://psychcentral.com/lib/opioid-dependence-and-withdrawal/0008507
--Opioid addiction is a disease of the brain. Repeated use of an opioid leading to opioid dependence causes long-term changes in both the structure (the architecture of the brain) and the way the brain functions (the biochemistry of the brain). Many use it outside of the prescription directions.
4.SAME AS 3
Tolerance: need more of the opioid to get the desired effect
the GI issues become worse with the increase in dosage – making the side effects worse than the pain-relieving benefits
Opioid drugs, such as morphine, have to be increased overtime to continue delivering an adequate amount of pain relief
-- previous reseach shows that we do have a possible solution. If we act on the NPFF system in coorelation with the opioid system, then tolerance will not develop.
No tolerance means no increased dosages. No increased dosages means less addiction and less harm to the GI tract.
--Previous research within our own lab shows that compound VBJ192 works due to testing performed on mice. However, it only works when injected directly into the brain. Noone wants to inject shots into their brain. Need to find a drug that will work orally. That’s where the BBB comes into play. The BBB is very picky. Does not work if something is
1.
That’s where the BBB comes into play. The BBB is very picky. Does not work if something is too highly charged, too large, not lipid soluble..
Also, if it is too basic. AND, we know that 5 Nitrogens within a structure is the max number of nitrogens that can enter the BBB.
Therefore, we would like to use SAR. Once we change different parts, we can try & enter the BBB. SAR will allow us to determine what part is necessary to have the desired function
As well as help us change structures to one that will pass BBB more efficiently.
For my compound, we used SAR and changed from guanidine to aminidine.
WHY?
amidine functional group has been shown to be able to penetrate the Blood-Brain Barrier (BBB) from peripheral administration when it has been substituted for the guanidine functional group.
Hoping the rest of the compound will work as VBJ192 did, but be able to penetrate BBB so we can make oral drugs.
Bromobenzene was added to triphenylphosphine, was dissolved in toluene, and refluxed at toluene’s BP overnight to yield the benzyltriphenylphosphonuim salt, which
Is needed to proceed with the Wittig Reaction.
97% yield
Used the salt made, combined it with benzylpiperidone & refluxed overnight in a solution of LDA. LDA was used in order to produce the YLIDE. (+ and - charge next to each other)
It was very important, at the step, to perform the reflux under argon, due to LDA’s reactivity with our air. LDA will take a Hydrogen, which destroys LDA’s ability, which stops the reaction
from taking place. Produced our desired compound, 1-benzyl-4-benzylidenepiperidine, and by product triphosphoniumoxide. After separating the two we proceeded..
42.2% yield
To bromination. This was a cool step. The bromine was a dark orange color with fuming orange vapors.
--let it stir, heated & added NaOH and MeOH. Did purification to just have desired product without any starting materials.
80.7% yield
We took our brominated product and reacted it with cynaopheynlboronic acid and tetrakis(triphenylphosphine) palladium. The palladium is air sensitive (used argon) as well as light sensitive. (Also, side note – makes a really pretty neon color show when put under UV light for TLC). So, we had to wrap the flask in foil to prevent the reactants from being exposed to light as it refluxed over night. This reaction added the phenyl group with the cyano to our compound. 52.1% yield
Then, came the last part of the synthesis. Converting the cyano group into amindine. THEORETICAL YIELD:
Gravity filtration in order to separate the different compounds of the mixture. Used this to separate the desired product from byproduct in Wittig reaction.
Chromotography to separate the compound for purity: use different mobile phases based of polarity that allowed for separation. We didn’t use pressure. Very time-consuming.
So, we made the compound, purified it, then verified it was the actual desired product in a purified form.
Different vials from Chromography. Used a sample of what we new was the compound (from previous column)
-verifies the mass of the compound
-shows that there aren’t detectable impurities because of single peak
. If the in vitro assays are in close agreement with VBJ-192, MCM1 will be investigated in vivo for antinociceptive activity through peripheral administration in Core D of the COBRE program, followed by investigation at Torrey Pines for acute antinociceptive tolerance.
--learned to be patient because chemistry doesn’t work on a planned schedule
--you will mess up; it’s a part of the practice.
Ex. Dropped stir bar into chemical waste bucket.