1 Neuroscience with Pharmacology 2 Neuromuscular Junction 2: Pharmacology Sir Henry Dale Acetylcholine “Quaternary” nitrogen + 1. Principles and methods for studying ACh pharmacology at the NMJ 2. Targets for drug action at the NMJ 3. Drugs affecting ACh Receptors (activation) 4. Drugs affecting ACh Esterase (inactivation) 5. Drugs affecting ACh release 6. Drugs affecting ACh synthesis and storage. Neuromuscular Junction - Pharmacology 1. Principles and methods Drugs acting at the NMJ are useful as: Experimental tools Clinical treatments • Target specificity/Ligand specificity • Agonist/Antagonist • Dose/Response • Efficacy (EC50/IC50)/Affinity (K D ) • Competitive/Non-competitive • Clinical/Non-clinical uses • Side-effects When “doing drugs” a good pharmacologist needs to know:
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Neuroscience with Pharmacology 2
Neuromuscular Junction 2: Pharmacology
Sir Henry Dale
Acetylcholine
“Quaternary” nitrogen
+
1. Principles and methods for studying ACh pharmacology at the NMJ
Reversible competitive antagonism of the ACh receptor. 1
dTC
ACh ACh
ACh ACh
dTCACh dTC
ACh
Reversible competitive antagonism of the ACh receptor. 2Drugs that block ACh Receptors (antagonists)
Example:d-tubocurarine
Example:α-bungarotoxin
ACh
αBTX
ACh
ACh
ACh
AChACh
AChαBTX
Irreversible competitive antagonism of ACh Receptor
Not broken down by AChE (nmj) Broken down by BuChE (blood plasma) Short lasting Not counteracted by cholinesterase inhibitor Used clinically for brief muscle relaxation “Depolarising blocker”
2
2
AcetylcholineSuxamethonium
6
dTC dTC neo sux sux sux neo direct
Sux
Na+
+
Na+
K+
+
Dual effect of suxamethonium (succinyl choline)
1. Depolarisation
Sux
+
Na+ Na+
K+
Dual effect of suxamethonium (succinyl choline)
2a. Sodium inactivation (depolarising block)
Sux
Dual effect of suxamethonium (succinyl choline)
2b. Desensitization of AChR (depolarising block)
Phencyclidine (PCP,”angeldust”)
Non-competitive antagonists of the nicotinic ACh receptor