botany of modern medicine- CNS & drugs

curare plants, indigenous tribes in South AMERICA WOULD USE IT TO COAT THEIR ARROW TIPS, (names) all are

nirtogenous compounds —>strychnos spp., malouetia, chondrodendron tomentosum (alkaloids)—>strychinine is also used as a rodent/pest killer but banned for organic agri

Phyllobates

(poison dart frog)

(poison dart frog) often used

curare to create muscle relaxants.

neuromuscular nicotinic receptors

control skeletal muscle depolarization

how does curare work

ACh binds to nicotinic receptors, it causes an influx of sodium ions, leading to depolarization and triggering muscle contraction. When curare or similar poisons bind to these receptors, they prevent this depolarization, so the muscle remains relaxed (curare, as an antagonist, binds to a receptor but does not activate it but blocks it)

analgesia

loss of response to pain

curare history

• spaniards ambush canoe with indigenous people, indigenous people defend with poisioned arrows

• full stomachs in animals had resistance to posion

• direct attack to muscle tissue, quickly succumbed

• affects lungs

• Details an ovariotomy where chloroform was used as an anesthetic.

• The patient experienced severe muscle contractions, which were controlled with curare, marking an early use of curare in anesthesia.

• also used in shock therapy, aid in surgical muscle relaxation

acetylcholinesterase

inhibited by anesthetics (curares), nicotinic receptor

tubocurarine, toxiferine cause

nicotinic antagonists cause muscle relaxation by antagonizing acetylcholine receptors

tubocurarine

derived from chondrodendron tomentosum, discontinued due to hypotension (black widows or latrodectus mactans poisonings would cause muscle spasms so tunocuraine would stop it

toxiferine

derived from strychnos, led to more effective alternate molecule since less long duration which would cause histamine release build up for hypotension

suxamenthonium

modern nicotinic antagonist derived from curare, desensitizes nicotinic receptors, no side effects, and can be used as a murder agent bc can paralyze muscles that you still need like diagram

also lowkey two acetylcholines make this molecule, makes sense to be an antagonist!

strychnine

derived from strychnos, antagonist of glycine receptor (inhibits hyper polarization), so contracting muscles A LOT, firing neurons! ANTAGONIZES glycine receptors, causing convulsions

ketamine and ect are

same basically for depression

glycine receptor

opens chloride channel and hyper polarizes cells (inhibits neurons)

-found in spinal cord, agonized by glycine (simplest amino acid), opens chloride channel to HYPERpolarize the cell (make inside more neg)

Stopping glycine receptors does what

stops hyperpolarization, making it way easier to depolarization bc less of a drastic change is needed

conium spp.

poison hemlock

coniine

compound in hemlock that antagonizes nicotinic acetylcholine receptors in neuromuscular and CNS/PNS, penetrates brain, paralyzes and goesinto cns!!

cicuta

cicutoxin, in water hemlock hemlock

water hemlock is a blank to gaba

antagonist of GABA receptors (similar to glycine receptor),

cicutoxin GABA Repolarizes, so w/o repolarization, very easy to depolarize

also causes convulsions coma death

GABA receptor

chloride channel that causes hyper polarization of neurons

cicutoxin

poison hemlock toxin that depolarizes neurons by inhibiting GABA receptors, deadly

capsicum annuum

hot pepper

capsaicin

compound found in hot pepper that agonizes TRPV1 and depolarizes neurons, can also desensitize TRPV1

reacts like to heat pr acidiosis, causes ca2+ inflow and na+ inflow in cell, depolarizes cell but this can be overloaded and cause defunctionalize so more spice needed , MAKES ION CHANNEL INACTIVE

woahh whats pepper spray made out of

capsaicin spray

therapeutic uses of capsaicin

neuropathic pain (adnormal PAIN with nonpainful stimulus), allodynia (pain to normal non painful ), postherpetic itch from shingles

TRPV1 agonists

ethanol (burning feeling, heat) , piper negrum (black pepper), zingiber officinale (ginger), brassicaceae (wassabi), garlic TRPV1

cannabis sativa

marijuana

cannabis hyperemesis

cannabis causes throwing up, nausea

Cannabidiol

compound found in marijuana that can be used in epilepsy treatment (CBD is not psychoactive)

THC

marijuana compound used in Tourette's treatment, BUT causes side effects so with cbd treatment need purified cbd oil to not be crazy for kids, helps with seizures!

Alzheimer's disease

impaired working memory caused by hyper-phosphorylated tau proteins and amyloid beta-peptide plaques

MCFAs and triglycerides, ketone bodies, ketogenic diet with medium chain triglycerides

potential Alzheimer's treatment, more mitochondria produced?

keto

fatty acid for energy, ketone. bodies causes high blood/tissue levels of mcfa

medium chain fatty acid supplement

lauric acid in coconut oil. cocos nucifera coconut or african oil palm, so axona, a medical food made from palm oil

Parkinson's disease

poor muscle control due to depleted dopamine activity (neuron death/degradation)

substantial nigra- involved in goal-oriented behavior

substantia nigra

An area of the midbrain that is involved in motor control and contains a large concentration of dopamine-producing neurons (diminished in Parkinson's)

medication cy

medication cycle for parkinsons

symptoms go away

med. fading effect, symptoms return

dopamine metabolism

dopamine cant enter CNS fron blood

only dopamine precursors can enter CNS,

synthesized in the brain from tyrosine and levodopa precursors (tyrosine, LDOPA), LAT1 transports these into brain

vicia faba

fava bean

fava bean

potential treatment for Parkinson's, contains L-DOPA and carbidopa dopamine precursors, eaten and was good!

glutamate, glycine, proline

amino acid neurotransmitters

dopamine (DA), serotonin (5-HT), DMT, GABA, epinephrine/norepinephrine

amino acid derivative neurotransmitters

omega-3 and omega-6

omega-3, omega-6 fatty acids give rise to eicosanoids, which are signaling molecules that help regulate inflammation

alpha linoleic acid(ala)

PLANT omega 3 —

but only 20% conversion rate to EPA AND DHA (animal fatty acid)

alagal oils

rich in DHA, ANIMAL SOURCES ALSO HAVE DHA AND EPA

Hempseed plant sources

have lots of ALA, like chia seeds

DHA , EPA, & CNS STATUS

ADHD have lower levels of DHA

fish oils must be unoxidized when consumed, esp when pregnant

most fish oil exceeded leves of oxidation

anterograde

learning new info whilst drinking, will they remember better than without?

somatostatin, substance P, opioids

peptide neurotransmitters

adenosine

purine neurotransmitter

acetylcholine (nicotinic), GABA-A, glutamate, glycine, serotonin are what type of proteins

ligand-gated ion channel neurotransmitters

acetylcholine (muscarinic), GABA-B, glutamate, dopamine, opioids, serotonin (not 5-HT3), cannabinoids, adenosine are what type of proteins

GPCRs

phenethylamines, what are there precursors and are these exogenous or endogenous

molecules like tyrosine that turn into dopamine, adrenalines, norepephrinephrine endogenous

phenethylamines

exogenouus, methamphetamine, mesacline, amphetamine

tryptamines (endo)

serotonin, tryptophan, melatonin, trptamine

Tryptamine exo

DMT, LSD, PSILOCYBIN, PSILOCIN

FDA Drug Classifications

schedule 1- abuse, no med, no safety

heroin, lsd, peyote, psilocybin, psilocyn., thc, cannabinoid salvia divinorum

schedule 2 -could abuse, has accepted medical use., may lead to psych or physical dependence

schedule 3- less version, but not too bad fl statute did

addiction

incessantly prioritizing one behavior over other behaviors

addictive substances typically enhance synaptic dopamine

rates experiment with addiction

so morphine consumption, social rats had less of a desire for morphine than the isolate males females

CNS Genetic variation

not everyone has the same responses to neurotransmitters or drugs

so A1 allele associated with less DA receptor density, so addictive behavior bc usually not too much da

seriotnin decreased SERT function. This variant is associated with an increased risk of psychiatric disorders, type-2 diabetes, and obesity. 

CNS neurotransmitter metabolism

1. Synthesis

2. vesicle release

3. reuptake

4. breakdown

Blood brain barrier

tight junctions help to restrict passage of molecules,

synaptic dopamine

agent enhanced in addiction

reuptake inhibition, what is IC50

indicated by IC50: how much of a substance is needed to inhibit a biological process by half

SO IF LOWER IC50 = STRONGER INHIBITION

receptor binding

indicated by Ki (dissociation constant), lower value = higher binding affinity

Ki, what is it

dissociation constant, likelihood of drug dissociating from membrane protein

lower values, stronger binding affinity

ephedra (phenethylamine)

plant species that contains ephedrine (stimulant), similar compound to epinephrine

amphetamines

explored as a substitute for ephedrine then noted for its stimulant properties

ephedrine was used as a decoestant. incr blood pressure. amphetamine also marketed as decongestant

adderall

amphetamine used in ADHD treatment(racemic mixture)

amphetamines

increase dopamine by inhibiting reuptake and MAO and causing reverse transport, upregulating TH

methylphenidate

synthetic molecule, has similar mechanism & structure to cocaine (ritalin) helps rita wife play tennis

erythroxylum coca, e novagranatense

cocaine

cocaine

stimulant with low Ki value and low IC50, triggers DA and 5-HT release, increased oxygen usage in various brain regions after coke administration

crack

cocaine + baking soda, more higher risk of arrest 500g to powder to 5 g to ccrack

cocaine overdose

increased adrenergic stimulation (norepinephrine), most likely through reuptake inhibition, followed by hyperthermia (feeling very warm), hypertension/vasoconstriction, and risk of heart attack, tachy-arhythmia, rly blocking reuptake protein

amphetamines seem to

be reuptaked with dopamine, leaving more dopamine outside of the neuron

cocaine OD treatment

cooling and benzodiazepines (enhance GABA receptor activity) which thus increases hyperpolarizatiins

snorting

common way to ingest amphetamines that increases risk of lesions in the back of the nose, necrosis, and adulteration (contamination of fentanyl and other substances)

catha edulis

khat

cathinone

compound found in khat that stimulates the release of DA and 5-HT, rather than cocaine that inhibits reuptake!

after harvest rapidly converts to cathine, looks like dopamine/adrenaline

MDMA

ecstasy

ecstasy

originally synthesized to treat/stop bleeding, known for increased social activities and increasing oxytocin levels , wont see negative mood in others

(during exploration of hydrastine and hydrastinine from Hydrastis canadensis)—increases dopamine release not inhibition

pKi, for MDMA

higher pKi, greater afinity, for MDMA big binder to 5ht2b

ecstasy side effects

brain hyperthermia, vasoconstriction, post use depression, with adulterants very dangerous

ecstasy benefits

potential treatment for PTSD

nicotine

nicotinic agonist that increases dopamine release, kind of mimics ACh

caffeine

purine molecule (like adenosine or guanine) that antagonizes adenosine receptors and inhibits phosphodiesterase

depressants

enhance hyper polarization, BECOME MORE NEG! Barbituates, benzodiazepines

depressants work by using

GABA

opioid receptors

GPCRs, four kinds including delta, mu, kappa, and NOP, hyper polarize cells by activating K export and inhibiting Ca import

activate K+ channels membrane hyperpolarization

ca2+ channels, decreased neurotransmitter release

endogenous opioid agonists

peptides (short chain amino acids)

endogenous opioid agonists

synthetic drugs, various plant molecules

endorphins

endogenous opioids that act on all four receptors, 5-31 amino acids long

1.opioid agonist inhibit/hyperpolarize GABA-releasing neurons

2. (double negative), so hyperpolarization of GABA inhibits GABA, so GABA will not be able to hyperpolarize DA-releasing neuron

3. dopamine is able to be released more readily

GABA releasing neurons

have mu opioid receptors that inhibit them and allow for the release of more dopamine

morphine

synthesized by papaver somniferous (opium poppy), acts on mu opioid receptors

exogenous opioids

codeine, morphine, heroin, fentanyl

whats an opioid antagonist

naloxone, (narcan)

EC50

half maximal effective concentration, lower value equates to a more potent drug

codeine

demethylated to morphine in vivo, also produced by papaver, analgesic addictive