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PIONEER PHARMA ACADEMY
GENRAL PHARMACOLOGY BOOKLET
TARGET OF DRUGS
Receptor classification
GPCR mechanism Steps
GPCR messengers
IP3/DAG Pathway
Examples of GPCR Pathways
Cellular effect Response via GPCR
Adenylyl cyclase:
cAMP pathway
increases
Increased contractility/impulse generation (heart), relaxation (smooth muscle), glycogenolysis, lipolysis, inhibition of secretion/mediator release, modulation of junctional transmission, hormone synthesis, etc. cAMP directly opens a specific type of membrane Ca2+ channel called cyclic nucleotide gated channel (CNG) in the heart, brain and kidney.
Phospholipase C: IP3-
DAGpathway
mediates/modulates contraction, secretion/ transmitter release, eicosanoid synthesis, neuronal excitability, intracellular movements, membrane function, metabolism, cell proliferation, etc.
Channel regulations
(Ca2+, K+ or Na+)
Physiological responses like changes in inotropy, chronotropy, transmitter release, neuronal activity and smooth muscle relaxation follow. The Gs opens Ca2+ channels in myocardium and skeletal muscles,
while Gi and Go open K+ channels in heart and smooth muscle as well as close neuronal Ca2+ channels.
G- PROTEIN – The G-protein consists of three subunits (α, β, γ), which are anchored to the membrane through attached lipid residues. Coupling of the α subunit to an agonist-occupied receptor causes the bound GDP to exchange with intracellular GTP; the α-GTP complex then dissociates from the receptor and from the βγ complex, and interacts with a target protein (target 1, which may be an enzyme, such as adenylate cyclase, or an ion channel). The βγ complex may also activate a target protein (target 2). The GTPase activity of the α subunit is increased when the target protein is bound, leading to hydrolysis of the bound GTP to GDP, whereupon the α subunit reunites with βγ.
G-protein-coupled receptors
- These are sometimes called metabotropic receptors.
- Structures comprise seven membrane-spanning α-helices, often linked as dimeric structures.
- One of the intracellular loops is larger than the others and interacts with the G-protein.
- The G-protein is a membrane protein comprising three subunits (α, β, γ), the α subunit possessing GTPase activity.
- When the trimer binds to anagonist-occupied receptor, the α subunit dissociates and is then free to activate an effector (a membrane enzyme or ion channel). In some cases, the βγ subunit is the activator species.
- Activation of the effector is terminated when the bound GTP molecule is hydrolysed, which allows the α subunit to recombine with βγ.
- There are several types of G-protein, which interact with different receptors and control different effectors.
- Examples include muscarinic acetylcholine receptors, adrenoceptors, neuropeptide and chemokine receptors, and protease-activated receptors.
Receptor-linked G-proteins also control:
- Adenylate cyclase/cAMP:
- adenylate cyclase catalyses formation of the intracellular messenger cAMP
- cAMP activates various protein kinases that control cell function in many different ways by causing phosphorylation of various enzymes, carriers and other proteins.
- Phospholipase C/inositol trisphosphate (IP3)/diacylglycerol (DAG):
- catalyses the formation of two intracellular messengers, IP 3 and DAG, from membrane phospholipid
- IP 3 acts to increase free cytosolic Ca2+^ by releasing Ca 2+^ from intracellular compartments
- increased free Ca2+^ initiates many events, including contraction, secretion, enzyme activation and membrane hyperpolarisation
- DAG activates protein kinase C, which controls many cellular functions by phosphorylating a variety of proteins.
- phospholipase A 2 (and thus the formation of arachidonic acid and eicosanoids)
- ion channels (e.g. potassium and calcium channels, thus affecting membrane excitability, transmitter release, contractility, etc.).
Enzyme receptors
ENZYME AS DRUG TARGET
The reasons why proteins (will refer specifically to enzymes here) make good targets is because:
- They have high structural specificity
- Tissue specific expression
- Species differences in enzyme properties.
- Although the enzyme may have the same name and
same function, there are slight chemical
differences between species which is exploited by species specific drugs.
- Enzymes act as catalysts for reactions
- Some enzymes work in cascade reactions.
- We must target the rate limiting enzyme because this
enzyme limits the rate of all the other
enzymes in the reaction cascade.
- Isoforms
- Most enzymes have more than one isoform.
- The development of drugs which target specific
isoforms can help in:
- Improving tissue selectivity
- Reducing side effects.
Mechanisms by which drugs interact with an enzyme
- Competitive inhibitors
- Bind to the same binding site as the substrate.
- Binding is surmountable
- Non-competitive inhibitors
- Does not bind to the same binding site as the
substrate.
- Pseudo-irreversible inhibitors
- Have high affinity to an enzyme and a slow off rate. The binding is non-covalent but because the affinity is
so strong, they can be considered irreversible.
- Irreversible inhibitors
- Bind to the enzyme with strong covalent bonds
- Allosteric activation
- Does not participate in a reaction.
- Binds to the enzyme and increases its catalytic ability.
- Binds to a site different from the substrate binding site.
- Substrates and false substrates
- Drugs can act as substrates, substituting for endogenous substrates with biological activity.
Types of enzymes targeted by drugs
- Enzymes regulating cellular metabolism
- Enzymes that pump ions (ion channel ATPases)
- Enzymes involved in homeostatic regulation
- Neurotransmitter/hormone synthesis
- Degradation or action of regulatory factors
- Blood clotting enzymes
COMPETITIVE EQUILIBRIUM TYPE INHIBITORS (Vmax Unchanged, Km increases)
Physostigmine and neostigmine compete with acetylcholine for cholinesterase.
- Sulfonamides compete with PABA for bacterial folate synthetase.
- Moclobemide competes with catecholamines for monoamine oxidase-A (MAO-A).
- Captopril competes with angiotensin 1 for angiotensin converting enzyme (ACE).
- Finasteride competes with testosterone for 5 2 32 9-reductase
- Letrozole competes with androstenedione and testosterone for the aromatase enzyme.
- Allopurinol competes with hypoxanthine for xanthine oxidase; is itself oxidized to
alloxanthine (a non competitive inhibitor).
- Carbidopa and methyldopa compete with levodopa for dopa decarboxylase. Physostigmine
and neostigmine compete with acetylcholine for cholinesterase.
COMPETITIVE NON EQUILIBRIUM TYPE INHIBITORS (Vmax Decreases, Km Increases)
- Organophosphates react covalently with the esteretic site of the enzyme cholinesterase.
- Methotrexate has 50,000 times higher affinity for dihydrofolate reductase than the normal substrate DHFA.
NONCOMPETITIVE EQUILIBRIUM TYPE INHIBITORS (Vmax Decreases, Km Unchanged)
Acetazolamide —Carbonic anhydrase
Aspirin, indomethacin—Cyclooxygenase
Disulfiram —Aldehyde
dehydrogenase
Omeprazole —H+ K+ ATPase
Digoxin —Na+ K+ ATPase
Theophylline —Phosphodiesterase
Propylthiouracil —Peroxidase in thyroid
Lovastatin —HMG-CoA reductase
Sildenafil —Phosphodiesterase-
