Cellular Receptor and Drug Action

A drug’s affinity for a receptor tells us how well the drug

binds to the receptor, but does not tell us anything about the action of the drug at that receptor

full agonists

bind to the same receptor site as the endogenous ligand and produce the same biological effect as the endogenous ligand at that receptor site

• identical to the hormone or ligand that the body produces

partial agonists

only a part of the endogenous effect is produced

inverse agonists

Bind to the same receptor site as the endogenous ligand, but induce the opposite response

• only happens when receptors have an intrinsic (basal) level of activity

• considered negative efficacy

• make the receptor less active (turn down the receptor)

Antagonists

bind to the same receptor site as the endogenous ligand, but DO NOT stimulate the receptor

• they occupy the receptor preventing the endogenous ligand from binding

Two main types of antagonists

1. Reversible (competitive and non competitive)

2. irreversible

Reversible, competitive antagonism

Antagonists compete for the same receptor binding site as the endogenous ligand

• competitive antagonist always dissociates from the
  receptor

Reversible, non-competitive antagonism

Binds to a site other than the endogenous receptor binding site “allosteric modulation”

Irreversible antagonists

An antagonist that binds to the receptor binding site and does not dissociate from the receptor

• K-1 = 0 and affinity is really high

G-proteins

stimulate effectors to produce

• Subgroups

  • Gs

  • Gi

  • Gq

G-proteins coupled receptors

Binding of a ligand to its receptor causes the G-protein to stimulate an effector

• ion chanels

• adenylyl cyclase

• Phospholipase

ion channels

Cardiac muscarinic receptor

adenylyl cyclase

makes cAMP from ATP

• camp is a second messenger

Phospholipase

PLC acts to cleave PIP and cleaved PIP yields IP3 and DAG

• P3 and DAG are both 2nd messengers

Cardiac atrial muscarinic receptor

Ligand binding at a receptor site leads to stimulation of a G-protein

• G-protein stimulation induces opening of an ion channel

• acetylcholine binds to the muscarinic
  receptor, the associated G-protein is stimulated

• The G-protein in turn activates the K+ channel to
  open

• K+ leaves the cell, hyperpolarizing the cellular
  membrane and slowing heart rate

Gs proteins

Stimulate adenylyl cyclase (the effector)

• Protein kinases activate enzymes by adding a phosphate group

Gi protein

Inhibits adenylyl cyclase (the effector)

• Activation leads in inhibition in cAMP since no new cAMP is made

Albuterol / salbutamol

(a bronchodilator) is a specific beta2-adrenergic receptor agonist

Misoprostol

(a peptic ulcer drug) binds to the Gi-linked prostaglandin EP3 receptor

• Receptor binding inhibits adenylyl cyclase

• cAMP production decreases

• Protein kinases are not activated by cAMP

• Enzymes and pumps that help produce stomach acid are no longer activated

• The production of stomach acid decreases

Phospholipase C (PLC) is activated by

Gq proteins

• IP3 binds to the sarcoplasmic reticulum and stimulates the release of Ca2 + into the cytoplasm

• DAG binds to calcium channels on the cell membrane, facilitating the movement of extracellular calcium into the cell

• Calcium influx into the cytoplasm (both pathways) produces the biological response

Ergonovine

binds to Gq-protein linked prostaglandin E1 receptors in the uterus and Gq-protein linked alpha adrenoceptors in the blood vessels

• Receptor binding stimulates PLC to produce IP3 and DAG

• IP3 binds to the sarcoplasmic reticulum and induces the release of Ca2+ into the cytoplasm

• Induces contraction of the uterus and blood vessels

• Can be used clinically to manage postpartum
  hemorrhage

cAMP

hold on to calcium