Upgrade to remove ads
Only $35.99/year

Pharmacology and Receptors

Terms in this set (143)

What is pharmacology?
-NOT PHARMACY
-The study of therapeutic drugs and their design
-How they work, how the body metabolizes them
-How to use out knowledge of diseases, Cell biology, neuro-biology, physiology etc to design new therapies
What is toxicology?
-Study if poisoning
-Harmful uses of drugs
-Drugs in humans, animals, and the environment
-How does poisoning work?
-How can it be treated-antidote
-Information provison to public-Avoid poisoning
What are drugs?
-A drug is a chemical that changes the behavior or function of individual system, organ, tissue or invading organism.
-To improve or not improve function
-Usually given intentionally for therapeutic reasons
-Drug effects are do to: A chemical interaction between the drug and the body
What are the sources of drugs?
-Plants
-animals
-Synthesized in the laboratoy
Describe Plants as sources of drugs
-The contain many different chemicals which can help the plant defend itself.
How do we use plants as sources of drugs?
-We don't use the extracts from plants, (to improve the safety), we get inspiration from them.
-We now usually isolate the compound and make it in the lab.
What are the benefits of making the plant replicate drug in the lab?
-We know exactly whats in it, and exactly how much of the active compound there is.
Whats some examples of plant drugs?
-Derivative digoxin still used for congestive heart failure.

-Hippocrates (HOOBC) advised patients to chew on willow bark to reduce fever and inflammation, ASPRIN is the derivative.
Animals and drug sourcing:
-Not so common anymore due to contamination issues.
-Many drugs mimic or block endogenous chemicals which are similar in all animals
-Originally got from animals because our metabolisms are quite similar therefore could isolate compounds from animals and out in the human to have a desired affect.
Example of Animal drug source?
-Thyroid supplement tables were made from dried thyroid gland tissue from animal.
-Used to treat hypothyroidism

-Insulin used for diabetes was previously all pork/beef insulin. But there was the fear of mad cow disease.

-Growth hormone used from animal cadavers- The creutzfeldt Jakob disease did occur and >100 people dies
Synthetic drug sources
-Lab work
-Most moderns drugs are synthesized in lab
How do you make synthetic drugs?
-Drug companies have millions of compound in chemical libraries which they use in high throughput screening with a specific drug target.

-In silico technology can be used, in which drug targets can be modelled on a computer.
What is the target of drugs?
-Drug binds to a molecule->effect. (molecular target)
Drug target..
Molecular -> Cellular -> Tissue ->System
Drug receptors
-'Reviever', the target of the drug, what the drug binds to.
-A drug can be designed to bind to anything,
What are examples of drug receptors?
Usually: Protein,
-An enzyme,
-cell surface protein, -protein in cytosol or nucleus
-DNA
The drugs effects happen through this molecule
What are physiological receptors?
-Subset of drug receptors
-Four types, of molecules moslty ones that span the membrane therefore- Transmembrane proteins
-DONT tend to be an enzyme lipid or sugar: USUALLY PROTEIN
-Extracellular and intracellular.
What is the purpose of a physiological receptor?
-Always signalling type molecules between outside and inside a cell-> links inside and out
What does a physiological receptor do?
-Regulates cell function
-It is NOT added- endogenous (native to the body)
-React with chemical messengers i.e: Hormones, neurotransmitters, growth factors.
What is a ligand?
Something that binds to a receptor
What is endogenous?
-Something that is native to the body, not added
What do you look for when you design drugs?
-A receptor which is already there
-Most synthetic drugs activate/inactivate receptors for endogenous substances.
-The lock and key model: Drugs need to fit the receptor for activation.
What are the four main types of physiological receptors?
-Membrane proteins coupled to ion channels
-Membrane proteins couple to G proteins
-Cytosolic proteins which couple DNA (NUCLEIC RECEPTORS)
-Membrane proteins couple to enzymes (KINASE RECEPTORS)
Agonist is?
-A drug OR endogenous molecule which binds to a receptor and can produce a full biological response
Antagonist is?
-Drug OR endogenous molecule which binds to a receptor but produces NO biological response.
-They keep the agonist from binding and producing a response
What are signalling pathways?
-Use lots of proteins normally
-Can be very complicated
-Taking an protein which activates another etc=CASCADE
How long does ligand/voltage gated channels take?
Milliseconds
How long does g protein coupled receptors take?
Seconds
How long does Kinase linked receptors take?
Minutes-Hours
How long does Nuclear receptors take?
Hours-Days
Ligand-gated ion channels
-A protein in the cell membrane
-Protein has a receptor domain (binding site for drug)
-And has an ion channel domain (lets the ions through)
Describe the structure of the Ligand-gated channel
-5 subunits
-The channel has a KINK, made from alpha helices which block the channel when close, when the ligand binds, the alpha helices unkind.
What does the binding of the drug do?
-Induces a conformational change.
-This allows certain things to pass through.
-ACh is commonly a ligand.
How specific is the ligand channel?
-It is a very selective pore
-Side chains only allow certain things to pass through
-Will only let certain ions through such as Na, K ,Ca,Cl
The movement of ions though the channel
-There are specialized receptors for different ions.
-Control of intracellular ion conc. is important, this gives selective transfer of ions in or out of the cell.
-IONS CANNOT MOVE THROUGH THE MEMBRANE
Example of ligand gated receptor: Nicotinic Acetylcholine receptor (nAChr)
-2 ACh binds to Nicotinic Acetylcholine receptors
-Causes an influx of Na+ ions into the cell and K+ ions out.
What is the endogenous ligand for the nAChr ?
ACh
What are the exogenous ligands which binds to nAChr?
-Nicotine
-Tubocuranine
Nictoine is what kind of drug?
-Nictoine is an agonist
-It acts on the nAChr on dopamine neurons in the brain
-This provides smokers a feeling or sensation-as dopamine is released
-Nicotine also acts on the adrenal medulla to cause adrenaline release
Tubocurarine is what kind of drug?
-An Antagonist.
-Many neuromuscular toxins block the nAChr like tubcurarine.
-Comes from Curare in south America, extracted in hunting and medicine.
-Muscle relaxer, too much will kill you by reaching the blood stream to the lungs-(respiratory paralysis)
-Low doses for medicine, against bruises, kidney stones, fever
Why can you eat the animal which has had tubocurarine in it?
It is irreversible binding
therefore wont effect the human
Voltage gated ion channels Structure
-4 Subunits
-There is no kink, but a lid like structure above the channel which is closed, until a stimulus tells to open.
How does voltage gate ion channels work?
-They are opened by voltage sensing segments, doesn't have a place for ligands/drugs to bind to.
-Sensitive to a difference in charge across the membrane
-Opens when a threshold has been met.
How specific are voltage gated ion channels?
-VERY specific for THEIR ion
Where are voltage gated ion channels found?
In neurons and other cells such as muscle
How are Voltage gate ion channels blocked?
-The drugs can block these ACTIVATED channels (lid off) directly.
-They insert themselves as a physical block inside the channel.
Examples of voltage gated ion channel inhibitors
-These are ANTAGONISTS
-Lignocaine (local anaesthetic)
-Tetrodotoxin (from puffer fish)
These block nerves so cant feel anything.
What are receptors?
-Most are transmembrane protiens
-Link between signals outside ad inside a cell
-extracellular and intracellular
Nuclear receptors
-Are carefull controlled because they interact with DNA
-Nuclear receptors are active in the nucleus
-They bind to DNA at a response element
Response elements are?
-Named after their receptor
-e.g oestrogen receptor (ER) binds to oestrogen response element (ERE)
-Weh the ligand receptor complex binds the response element the gene is activated
-Place on DNA where the dimer binds to
What is the process off nuclear receptors?
-Ligand must enter the cell, for receptor binding to occur in the cytosol
-Ligand causes receptor to dissociate from heat shock protein
-Nuclear receptor and ligand become a dimer
-Moves into the nucleus
-Binds to the response element in the DNA
What is a heatshock protein
-Like a chaperone, it looks after the nuclear receptor keeiping it inactive, preventing it from binding into the DNA, and other nuclear receptors.
Dimer
What the ligand a nuclear receptor become, once the heatshock protein leaves.
-Binds to hormone response elements
-Must also bind to DNA polymerase and transcription factors.
Why can nuclear ligands cross the membrane?
-Most are hormones, which are lipophillic and can cross the membrane
What happens after that?
-Goes transcription -> New mRNA -> translated -> New protein -> moved to new cells and carries out its function
What is the structure of the nuclear receptors?
-Located in the cytosol.
-3 Important parts:
~Steriod recognition site: binds ligand
~DNA binding domain" binds to DNA, has two zinc fingers in it- common shape
~Transcription regulatory domain: Binds other proteins: i.e DNA Polymerase, transcription factors
What is a key feature of the DNA binding site?
The zinc fingers- 2 Zn
What does the transcription regulatory domain bind?
Other protein: DNA polymerase and transcription factors.
Response time for nuclear receptors?
Hours to days
Which gene is activated depends on what?
-Ligand or drug
-Specific gene
-Cell type

Oestrogen will bind to oestrogen receptor: but it regulates heaps of things like : bone density, liver:cholesterol production, uterus: growth of cells etc. so with so many effect produced from one receptor, its location and gene target determine its function
Nuclear receptors in cancer
Two of the most common cancers are hormone driven- breast and prostate.
-Cancers are groups of cells that have matured to grow unconditionally and avoid cell death.
-hormone receptors are nuclear receptors.
The androgen receptor
-For testosterone
-95% is produced in the testees, 5% in the adrenal gland.
-Testosterone binds to the androgen receptor
-Mutated in cancer, the response to the hormone can not be turned off.
Tamoxifen
-Is a antagonist in mammary tissue.
-In breast cancer it stops cell growth
((-also An agonist in bone and uterine tissue))
-In agonist it it stops bones loss, and can result in endometrial cancers
Tamoxifen as a preventative
- A number of studies have looked at long term use of tamoxifen as a breast cancer preventitive
-Lowered risk of of 48% postive endometrial cancers
-Treatment lasred 4-8 years follow up for around 10
-Higher rate of endomemetrial cancer
-Fractures were reduced.
Prostate Cancer: Androgen deprivation therapy
-Stop testosterone production
-Surgery to remove testees
-Could either/or have chemotherapy which includes antiandrogen-act as an antagonist receptor, called biculutamide.
The adrogen receptor atagonist blocks, and accelerates the rate of receptor degradation
Biculutamide is?
-An antagonist, for the androgen receptor
- blocks the receptor
-Accelerate receptor degradation
-way to prevent excess testosterone for prostate cancer
What are teh problems associated with using antiandrogen therapy?
-Reduced libido
-Hot flushes
-tiredness
-decrease body hair
-decrease muscle and bone (strength)
-Weight gain
-Breast development
-Castration or further hormone therapy can prevent the rise in oestrogen level though oesteoporsis is still a problem
Oestrogen in water ways
-Feminization of fish has been noted near waste water treatment plants world wide
-Male intesex fish with ovaries
-Correlates with increased levels of oestrogen related compound in water
oestrogen mimics humans? Biphenal A
-Biphenal A in plastics and epoxy rexins
-low levels of exposure
-Tested as artifical oestrogen in 1930's but 37,000 times less effective than actual ostrogen
-May bind very strongly to a rare version of osetrogen receptor
-Possible health issies from exposure during pregnancy and development
-Some countries have banned it use in baby bottles, others declared save
-Has been found to accumulate in humans
-Effects may be neurological development, obestity, cancer
oestrogen mimics humans? Phytoestrogens
Plant osetrogens, for example soybean thought if you consume alot of soy it may change your endocrine system
How do drugs work?
-Binds to a receptor
-Conformational change
Receptor theory
-Lock key - drug and receptor
- key fits in lock- Drug has receptor specificity
-door opens-cellular effect
-Turn the knob- Conformational change
Why are G-coupled proteins important?
-They are the largest class of surface receptors therefore easy to target
-They are activated by a diverse arrange of ligands incl: Hormones, Neurotransmitters
-Represents the target for more than30-50% of drugs
G-couple proteins:
-Receptor coupled to a G-protein
-Found in the cell membrane
-Once an agonist binds to the receptor, the G protein becomes activate: conformational change
What happens once the G-coupled receptor is activated?
It'll increase or decrease the activity of an enzyme
What does the enzyme of the G-couple receptor do?
-The amount that the of second messengers in the cell, either increase or decreease
-It is change in second messenger amount that alters the physiology/biochemistry of the cell
What do second messengers do?
-They can release Ca2+
-They can phosphorlate a protein
-Other
this gives the cellular effects
second messenger dependant
The type of second messenger is dependant on the G protein
-I.e cAMP
G-coupled protein agonist examples
Dopamine-neurotransmitter
-Involved in the movement and ability to precieve reality
-Dopamine activates dopamine G-coupled receptors
Parkinsons disease
-Come from having low levels of dopamine receptors
-Dopamine receptor agonists are uses to treat it.
-Neurodegenerative disease
characterised by: resting tremor, brady kinesia, rigidity, postual instability
Levodopa
Is a prodrug that is metabolized into dopamine and dopamine then goes to activate the receptors.
How doe levodopa treat parkinsons?
-In normal people= normal levels of dopamine
-In a parkinsons person there is a loss of dopamine neaurons. Levodopa metabolizes dopamine and helps to control the move.
-Levodopa activates the g-protein
-Activates the enzyme
-The enzyme inhibits/turns down the second messenger
-Allows for movement
What happens to a person with parkinsons
-Low dopamine neruons
-No dopamine
-No dopamine receptor activation
-Uncheck second messenger signalling
Problem with levodopa
-With chronic treatment you get:
-Psychological effects
-Psychosis: hallucinations, perceiving what reality is
-Motor complications: Dysicinesia: dance like movement, uncontrolling
Why use a antagonist?
-When theres to much neurotransmitter floating around - disease states can be due to t much receptor activation.
-An antipsychotics= antagonist
What is antipsychotics?
Act as an antagonist at dopamine receptors
- used to treat psychosis= the inhibility to perceive reality= disillusion, hallucinations, commonly seen in schizophrenia
How do antipsycotoics treat psychosis
-High levels of dopamine receptor activation
-Antipsycotics stop the excess dopamine activating the receptor
Psychosis
-High levels of dopamine receptor activation
-Over activation of G protein
-Over activation of enzyme
-over activation of second messenger =(Massive decreases)
-Abnormal cellular response
Pyschosis with an antipsychotic
-The antiphsychotic block the dopamine at the dopamine receptor activation
-Stop G-protein activation, still a little active.
-And stop second messenger
=No psychosis
Problem with antipsychotics
Can induce parkinsons disease like symptoms
ITS HARD TO GET THE BALANCE RIGHT
-Parkinsons disease= too little dopamine receptor activation
-Levodopa= increases dopamine receptor activation, but acting as an agonist
-Side affect= pyschotic like symptoms

-Psychosis- too much dopamine receptor activation
-Antipyschotics= reduced activation by acting as an antagonist
-Side affect= parkinson like sympotoms
What do membranes allow?
To give diversity
-Separation of function
-Exchange of molecules
What is amphipathic mean?
A molecule, that has hydrophillic and hydrophobic parts
Amphipathic molecules of membranes- desciribe them
-16-22 length of hydrocarbon chains
-Non-polar
-Polar part is the phosphate group
-Commonly have a even number of carbons
-Can be saturated or non
Amphipathic molecules in a aqueous soloution
=Phospholipid bilayer
-They naturally self assemble in bilayers-this is an energetically favourable state 'likes dissolve likes'
-Bilayer= polar parts on outside and inside which are exposed to the aqueous solution
-non polar parts end up in the middle=away from aqueous soltuion
Structure of the fatty acid
-Membrane lipids have a glycerol backbone H2COH-H2COH-H2COH-
-The fatty acid (X2) at the glycerol back bone occupying two of those spaces, they can be different
What attatches to the third position on the glycerol back bone?
-A phosphate group
Phosphatidic acid is?
-The generic form with 2 fatty acids and phosphate group
-Only 10% of membrane lipid are in this form
What is the comopostion of a fatty acid?
CH2-(CH2)n-COO-
-COO- + OH (from glycerol) (ester bonds)
What is more often than not attatched to the polar group off the glycerol back bone?
-Another polar group is usually attatched to the phosphate caled phosphatidyl ester
Phosphatidyl ester is
-When another polar group is attatched to the phosphate
-Could be:sugars another phosphate etc
-E.g ethanolamine and choline are both charge therefore generate patches of charge at the surface of the membrane is can be useful for binding proteins
Other types of membrane lipids: Sphingolipids
-Bases sphingosines (amino acids) instead of glycerol
-Abundent in myelin sheaths around nerve cells
Other types of membrane lipids: Glycolipids
-Side chains attatched by glycosidic (sugar like) linkages
-common in plants
Membrane fluidity
-The membrane isnt fixed and rigid, things more within the membrane
-Lipids and proteins can move within the membrane
-It cant be rigid, because you need to be able to move things in and through the membrane
What affects the fluidity of the membrane?
-Temperature
-Length
-Type of fatty acid
Temperate as effecting the fluidity
-This could convert fat between solid and liquid
-Heat gives energy, energy can break non-covalent bonds
-That makes it go from a ordered state -> not ordered state.
Hydrophobic interactions
-Non-covalent
-Weak
-The further the distance between these non-covalent bonds, the weaker they get
Length the effects fluidity
-If you increase the number of carbons, you increase the melting point. (go from ordered->non ordered)
-More stable (stronger interactions) with a linger hydrocarbon chain
-Therefore the more hydrocarbons there are the more rigid the membrane would be.
Type of fatty acid effecting fluidity: saturated
-more saturated the fatty acid, the higher the melting point.
-saturate means no double bonds.
Type of fatty acid effecting fluidity: Unsaturated
-Have increased the distance between the hydrocarbon tails. therefore have weakening the interactions
-They are more difficult to order because of increased distance between fatty acids.
-If you weaken the interaction the make the mebrane more fluid/less rigid
-Therefore the more unsaturated fatty acids, the greater the fluiditity.
How have animals adapted in colder climates?
-They will tend to have a higher proportion of unsaturated fatty acids in there membrane because they don't want their membranes turning into butter/rigid when cold
How have animals adapted in warmer climates?
-Tend to find they dont want their membranes turning to fluid, tend to be more saturated, longer chains.
Presence of cholesterol
-Can stiffen the membrane
-Ring structue, relatively rigid, can act as an anchor point
-Rigid for lipids to bind to
Lipid bilayers are 2D fluids
-Lipids are not stationary within the membrane, they are moving
-They tend to movie in their own half of the bilayer(leaflet)
-They dont often flip from one side to the other because then they'd need to take the phosphate through a hydrophobic environment
Membrane proteins
-In general theres alot of proteins in the membrane. Varies between cells
-These proteins can move in the membrane as well.
Functions of membrane proteins:
-Cell to cell contact (desmosomes)
-Surface recognition
-Cytoskeleton contact
-Enzymes
-Transporters
-Receptors and signalling
Proteins can be integral or peripheral
Transmembrane proteins (extracellular and intracellular)
-Arrangement of amino acids in the proteins have to do with how the protein stays there.
-So kinds of amino acids found in the part of the protein which is in the middle of the membrane are like :Val, Ala, Phe all non-polar amino acids
-Parts of the protein which are exposed to the edges of the membrane are non-polar amino acids.
-Its the hydrophobic aminoacids which anchor the protein into the membrane
Peripheral protein
-I.e Glu and Asp are acidic
- there could be positive charges on the membrane form the third position on the phosphate.
-Therefore a protein may have alpha helixs on it with alot of Gly/Asp, which will interact with positive charge on the phosphate= electrostatic interaction, this could help hold the protein to the membrane
Proteins partially inserted in the membrane
-Mostly on the outside
-Like a boat. Anchoring domain to hold the protein in place called hydrophobic domain
-Structures withing the membrane are predominated by non-polar amino acids
Fatty acids can be used to anchor proteins in membrane
-Post translational addition of lipids=Lipidation
-Attatch on the protein,either side cahins or an end of a protein fatty acids
-This can anchor/hold the protein in place
The two sides of a membrane
-Are assymmetric
-Things may be specifically located on either outside or inside or maybe both.
-E.g sugars on proteins (glycoproteins) are destined found on the extracellular surface)
Transport of non-polar molecules
-Is dependant on hydrophobicity and concentration
-O2 and Co2 Oestrogen etc, some are more hydrophobic than others.
-Depending on how hydrophobic it is, can influence its ability to get across a membrane
What effects how a molecule can cross a membrane?
-How hydrophobic it is
-Size
-Concentration
Permeability co-efficeint
-Y axis,
the number gives an idea of how easy it is for a molecule to get across a membrane
-Small number= membrane is less permeable so that is is harder for the molecule to cross
-Bigger number means more permeable, gets across easier
Transport of polar molecules
-Most of membrane is non-polar, therefore a problem for polar thig
-The lipid bilayer represent an energetic barrier for the transport of polar molecules
-Need to lower the energy barrier
-Proteins make holes in membrane generating a polar hole=Channels and transporters
-Oil-water partition co-efficent
-X axis
-Smaller number the less hydrophobic/ non-polar the molecule is
-The greater the number, the more hydrophobic/non-polar the molecule is
Concentration gradient for determining how well a molecule can cross a membrane
-Y axis= J looking thing, which stands for movement/flux, the higher this number the you increase the transport going through a membrane

-X axis is concentration gradient
-[A]out-[A]in, the greater the conc. gradient the higher the rate of transport
Channels
-When open a channel is open to both intracellular and extracellular space.=span membrane
-Can be opened/closed spontaneously or be 'gated'
What is the rate of transport for channels?
-Can approach rate of diffusion of 10^7-10^8 molecules per second.
Aquaporin
-Water channel
-Billion water molecule per second
-There are vestibules at either side of the channel where you have lots of water molecules able to gather, then the channel narrows through the middle
Transporters
-Are open to either the intracellular or extracellular space and closed at the other
-The binding of substrate induces a conformational change in the protein. (closes at top, opens at bottom) opens to release the molecule to the other side, then goes back to its original shape.
Rate of transport of transporterss?
-10^2-10^3 molecules per second
-Generally used for larger molecules
Transporters are selective
-Can distinguish between molecule, even if very similar
Kinetics of facilitated diffusion
-All similar to enzymes
-Ja= velocity/rate
-Km=substrate conc. which gives 1/2 the Jmax of velocity of transport
-same rectangular hyperbole
Non-mediated
-Does not require a protein
Ja=
Ja= Jmax[A]
Km + [A]
Passive
-Down its conc. gradient (no exogenous energy required)
Mediated
-Uses protein-also called facilitated transport
Active transport
-Requires input of energy to move a molecule up it conc. gradient
-Energy may com from the hydrolysis of ATP, or co-transport of another molecule down its conc. gradient
Co-transport
-Movement of two molecules by a transpot
=Symport/Anitport
Symport
Both molecules move in the same direction
Antiport
The two molecules move in opposite direction
Na/K ATPase
-Phosphorylation of pump, where energy comes from to drive transport we use ATP, to phosphorylate one of the side chains of the pump, and you get a conformational change.
-When you dephosphorylate- the reverse happens, one end opens the other closes.
Sets found in the same folder