531 Lec 24-25

Neurotransmitters

chemical messengers that transmit signals from a neuron to a target cell across a synapse 

List of events for neurotransmitters

1)Usually synthesized in presynaptic neuron

2)Localized to vesicles 

3)Impulse

4)Fusion of vesicle with presynaptic neuronal membrane

5)Release of neurotransmitter into synaptic cleft

6)Interaction of messenger with post synaptic membrane receptors 

7)Receptor-messenger engagement elicits biological response

8)Removal of NT from cleft

Amino Acid Neurotransmitters

Glutamate

GABA

Biogenic Amines NTs

Norepinephrine

Epinephrine

Dopamine

Serotonin

Histamine

Peptide NTs

Endorphins

Acetylcholine

•Inhibits smooth heart muscle

•Constricts gastrointestinal muscles

•Extensively active throughout brain synapses

•Released at all vertebrate neuromuscular junctions

Ach effects on periphery

Decreases heart rate

Increase Bronchoconstriction

Increased skeletal muscle contraction

Increased GI and urinary muscle contraction

Ach effects on CNS

increased memory

increased thinking

Ach Synthesis

1) Serine gets decarboxylated via serine decarboxylase

2)Choline is formed via choline N methyl transferase

3) Acetyl choline is formed via choline acyltransferase with acetyl COA as a co substrate

Ach breakdown

Acetylcholinesterase and water break Ach into acetic acid + Choline

Ach Receptor signaling pathway

1)Impulse comes through axon

2)Impulse causes influx of calcium ion

3)Calcium oin binds an ACh vesicle

4)Vesicle fuses with membrane and releases Ach into synapse

5)Ach binds either nicotinic or muscarinic receptor on next neuron OR it can diffuse to a nicotinic autoreceptor or muscarinic autoreceptor on same neuron and get re uptaken OR hydrolyzed by AchE

Muscarinic

• M1-M5

•G protein coupled receptors → second messenger cascade 

•Natural ligand known as muscarine, low affinity for nicotine 

Nicotinic

•Nm- muscular

•Nn- neuronal 

•Ganglionic

•Ion channels

•Natiral ligand known as nicotine , low affinity for muscarine 

Acetylcholine Binding with Muscarinic Receptors

•Hydrogen bonding: ester and Asn-617

•Hydrophobic interactions of ethyl middle section

•Ionic bonding: quaternary amine and Asp311

•Methyl groups fit into small pockets

Ach Binding with AChE

Cation Pi interaction

Hydrogen bonding

\
Serine, histidine, glutamic acid

Therapeutic Uses of ACh

stimulates muscle contraction, involved in REM sleep, cognition and neuroplasticity 

→Excessive Ach at the neuromuscular junctions and synapses cause symptoms of both muscarinic and nicotinic toxicity; cramps, increased salivation, lacrimation, paralysis, diarrhea, blurry vision, muscular fasiculation

→Low levels of ACh can lead to muscle weakness, memory, focus, thinking issues and other neuologica conditions 

SLUDGE

Structure Activity Relationships (SARs):

an approach designed to find relationships between chemical structure (or structural-related properties) and biological activity (or target property) of studied compounds.

SARs for Muscarinic Drugs

1)Ing’s Rule of 5

2)The molecule must possess a nitrogen atom capable of bearing a positive charge, preferably a quaternary ammonium salt

3)For maximum potency, the size of the alkyl groups substituted on the nitrogen should not exceed the size of a methyl group

4)The molecule should have one oxygen atom, preferably an ester like oxygen capable of participating in an Hbond

5)There should be a two carbon unit between the ester oxygen atom and the nitrogen atom

Ing’s Rule of 5

Max cholinergic activity occurs when there is no more than 5 atoms from nitrogen to the terminal hydrogen atom on the acyloxy group

Methacholine chloride

•Muscarinic receptor selective

•Muscarinic agonist

•Low activity at nAChRs

•Bronchiospasm test for asthma

•Inhaled powder

Carbechol chloride

•Binds mAChRs and nAChRS- agonist 

•More restsant to base, acid that ACh

•More resistant to AChE than ACh

•Weak inhibitior of AChE

•Longer duration of action

•Use: glaucoma

•UseL Induce miosis during surgery

•Opthalmic solution

Bethanechol Chloride

•Carbamate analog of metacholine

•Muscarinic receptor selective

•Muscarinic agonist 

•Virtually no activity at nAChRs

•Use: treat postsurgical urinary retention

•Use: treat postsurgical abdominal distention

•Oral drug

Pilocarpine hydrocholirde

•Natural product

•M3 receptor selective agonist

•Penetrates the eye well

•Use: Glaucoma

•Use: dry mouth due to radiation therapy 

•Tablet, opthalmic solution, gel

Cevimeline hydrochloride 

•Natural product

•M1 receptor and M3 receptor selective agonist 

•Use: dry mouth due to radiation therapy

•Oral tablet