lec 1- receptors Flashcards
what is the definition of receptors
Naturally occurring receptors are molecules that bind signaling molecules (neurotransmitters, hormones etc) and activates cells as a consequence
- Any molecule that can be target for a drug
- Paul Erlich 1913
Nature of the drug targets
proteins
DNA- anti-cancer and some antibiotics
Carbohydrates and lipids- antibiotics
proteins targeted can be inside or outside of the cell
however, most target outside the cell as the membrane can be hard to get through
Name some Natural receptors
GPCR- muscarinic, adrenergic, histamine
Ion channel- nicotinic receptors
Gene transcription (steriod)
Enzyme- tyrosine kinase, guanylate, cyclase
Other drug targets
- Carrier proteins- transporters and pumps
- Voltage gated- Na channels, ATP dependant K channels,
- Intra or Extracellular enzymes- Ach esterase, COX-1 and 2
What can drugs do
- Agonists - activate receptors
- Antagonists- Deactivate receptors
- Some drugs can show mixed behavior, agonists in some situations and antagonists in others
Agonists
-Bind to receptors (agonist-receptor interaction)
-Causes a conformational change in receptor leading to activation (agonist-induced response)
-If the receptor is fully activated, the drug is a full agonist
-If the receptor is partially activated, the drug is a partial agonist
Agonist + Receptor –> Inactive AR complex –>
Active AR complex
potency
- Measures how much drug you need to add to get a response
- The conc of a drug that produces 1/2 the max response is the Ec50
- It is dependant on how well the drug binds to the receptor (affinity), how well it can activate the receptor (efficacy) and the number of receptors
- NB receptor density
Max response
Emax depends on the nature of the agonist= NOT all agonist give the same sized response
- Depends on the number of receptors in tissue
- Depends on how well the drug can activate those receptors (efficacy)
Affinity
-Affinity describes how tightly a drug (agonist or antagonist) binds to the receptors
If typically measured by the dissociation constant Kd= the conc of the drug needed to occupy 50% of the receptors
-This is known as the dissociation constant Ka
Efficacy
- Efficacy describes how well an agonist can activate a response once bound
- A partial agonist may have a high affinity (binds readily) but a low efficacy (doesn’t activate receptors well)
efficacy graphs- see notes
1) full agonist have high efficacy (A+B)
2) Partial agonist have intermediate effect
3 antagonist have ZERO effect
partial agonist and selectivity
Partial agonist benzodiazepine are anxiolytic but not sedative
- They are prescribed for anxiety and insomnia
- Partial agonist benzodiazepines can stimulate enough to make them anxiolytic but never enough to make them a sedative
spare receptors
- In many tissues there are for more reception that is needed to cause the max response, this displays a receptor reserve and has many spare receptors
- With spare receptors, get a max response whilst occupying a small % of the receptors
- The partial agonist can appear as full agonists if they activate enough receptors to reach Emax
The implication of receptor reserve
- Spare receptors aren’t in all receptor population, it is often found in smooth muscle (and those that respond to hormones)
- Receptor reserve can be seen as a defence mechanism, proportion of the receptors can be inactive but we can still achieve Emax
- A tissue may increase the number of receptors in order to be more responsive to lower conc of agonist
e. g. hyperthyroidism results in an increase in the number of cardiac B-receptors and thus the sensitivity of the heart to circulating catecholamines is increased
example of receptor reserve
Hyperthyroidism results from an increase in cardiac Beta-receptors and thus an increase in sensitivity of the heart to circulating catecholamines is increased
Antagonist
- Binds to the receptor to stop natural ligand from binding
- Many receptors show slight basal activity (lowest level of activation), even if no ligand is bound
- If the antagonist can also stop the basal activity this is known as an inverse antagonist
Competitive antagonism- Isoprenaline and propranolol in isolated GP atria
NB progressive shift to the right with no change in slope (See BB graph)
-A competitive antagonist competes for some sight as the agonist- therefore response doesn’t occur
-Inhibition can be surmountable- can be overcome by increasing conc of agonist, decrease conc of antagonist
RESULT
-A parallel shift in the conc-effect curve to the right
-No reduction in max response
-Linear Schild plot
irreversible or non- equilibrium competative antagonism
-The antagonist dissociates very slowly or not all from receptors
-This inhibition is non-surmountable the proportion of receptors occupied by the antagonist is lost to the agonist
-Max response decreased
N.B- complications arise in case of spare receptors
Receptor pharmacology: Definition
- Pharmacology is the study of drug action
- Molecular pharmacology aims to describe this in term biochemistry. The discipline underpins attempts to discover new drugs and therapeutic strategies as well as addressing fundamental questions in biology how how cells communicate with each other
Concentration curves
- Relate response to drug concentration
- Plot Conc on X axis
- Plot response on Y axis
- Can see potency which is how much drug we need to add to see a response
- Ec50= conc of drug needed to active 50% response (half the receptors)
- PEC50= -Log (like pH)
Characteristics of partial agonists: potential for selective effects
- Full agonists produce the max response of which the system is capable
- Partial agnostic are only to produce a sub maximal response at full receptor occupancy
Use of irreversible alkylating agents to demonstrate spare receptors
- Use agonists which slowly destroy receptors
- Alkylating agents once bound destroy receptor
- For a while we see that the sensitivity is decreased yet we still see Max response seen
- Once the reserve is gotten rid of and max response is now not seen
Non-competitive or allosteric antagonists
- Antagonist doesn’t compete directly for binding to agonist site but acts elsewhere on the receptor e.g. hexamethonium blocks the ion channel of the nicotinic receptor
- Result- decreased max response (similar to irreversible antagonist) but may also have complex effects on the slope of the curve
