Exam 3: Cholinergics Part 1 Flashcards
What are the 2 components of acetylcholine?
Acetyl ester and quaternary ion
Draw the structure of acetyl choline
What structures was Ach get broken down into?
Acetic acid and choline
How is ACh biosynthesized?
Choline acetyltransferase transfers acetyl group from acetyl CoA to choline
What is the limiting factor of ACh biosynthesis?
Choline that is recycled and biosynthesized from Serine
What does ChAT come from?
Biosynthesized in the cholinergic neuron
What is the function of acetylcholinesterase (AChE)?
Serine hydrolase enzyme that hydrolyzes of ACh forming choline and acetate also inactivating ACh
Describe the acetylcholine metabolism process?
What is tranesterification?
Transferring the ester group from ACh to the Ser-AChE complex while cleaving the choline.
What makes an ACh enzyme drug successful?
Ability to bind to the same receptors as ACh
What type of bonds are developed between receptor and ACh?
H from histidine will H-bond with the cholinergic ester. Tertiary nitrogen ionically binds with anionic binding site. Hydroxyl serine attacks the carbonyl carbon.
What is the purpose for fast ACh metabolism?
Each synaptic vesicle contains a lot of ACh molecule over receptors. AChE metabolizes it present overstimulation
What are the 2 types of cholinergic receptors?
- Muscarinic
- Nicotinic
How does this molecule match the SAR of Ach?
Muscarine: Tertiary ionized nitrogen, 2 carbon bridge, esteratic lone pair
How does this molecule match the SAR of Ach?
Nicotine: Tertiary ionizable nitrogen, 2 carbon bridge, 2 nitrogen contains lone pairs
What is the function of this molecule?
Pirenzapine: only muscarinic antagonist to block gastric acid secretion at concentrations that did not block the effects of other muscarinic antagonist
Where are M1 receptors located?
Neural tissues and various exocrine glands
What is the function of M1 receptors?
Involved with memory and learning implicated with Alzheimer’s
Where are M2 receptors located?
Postganglionic membranes in the ANS (smooth muscle, heart, exocrine)
What is the function of M2 receptors?
Decreases both the rate and contractility of the heart
Where are M3 receptors located?
Brain, smooth muscle, and secretory glands
What is the function of M3 receptors?
Brain: decrease neurotransmitter release
Smooth muscle and glands: contraction and secretion
Where are M4 receptors located?
Smooth muscle and secretory glands?
What is the function of M4 receptors?
Inhibition of calcium channels
What molecule was used to identify and study muscarinic subtypes?
McN-A343
Where are M5 receptors located?
Brain and peripheral tissues
What is the function of M5 receptors?
Whole tissue response in places that match expressed gene products
What are SAR requirements for muscarinic agonists?
- Esteratic site
- Anionic site
- 2 of the alkyl groups bound to tertiary N must be methyl groups
- ACh is not chiral, but receptor has chiral agents
- Follows ing’s rule of five
Describe the difference between esteratic and anionic sites of muscarinic agonists?
E: Acetyl ester oxygen undergos H-bonding
A: Quaternary nitrogen undergos ionic interactions
What is Ing’s rule of 5?
All potent cholinergic agonists have only 5 atoms between the tertiary nitrogen and terminal hydrogen
What can we expect from this ACh conformation?
180 degrees, antiperiplanar containing steric bulk therefore is the lowest energy conformation
What can we expect from this ACh conformation?
60 degrees, synclinal is the observed state in NMR and X-ray solid crystalline form
What can we expect from this ACh conformation?
137 degrees, anticlinical is the most active conformation is ACh receptors
What is the difference between cis and trans ACh?
Cis mimics synperiplanar which is eclipsed and sterically unfavored
Trans mimics anticlinal conformation which is favorable
What are the classifications of cholinergic and anticholinergic drugs?
- Muscarinic agonsits
- Acetylcholine inhibitors (reversible and irreversible)
- Muscarinic antagonists
- Nicotinic antagonists
Describe the characteristics of this drug?
- Muscarinic and nicotinic agonist with poor therapeutic agent
- Low bioavailability and nonselective action
- Quick onset and short duration of action
What is the therapeutic use of ACh?
Ocular surgery causing complete miosis (constriction) in seconds, instilled in the anterior chamber
Describe how ACh properties changes altering A?
- Increasing length of acetyl ester decreases potency
- Aromatic and high MW esters provide cholinergic antagonists
- Carbamates increase stability to hydrolysis from AChE
Describe how ACh properties changes altering B?
Equipotent, Methylation of beta carbon shifts affinity towards muscarinc selectivity
Describe how ACh properties changes altering C?
Less potent, Methylation of alpha carbon shifts affinity towards nicotinic selectivity
Describe how ACh properties changes altering D?
Activity decreases as chain length increases
Describe how ACh properties changes altering E?
3 methyl groups are optimal for activity, removal of methyl reduces activity. Replacing all methyls with ethyls results to antagonism, replacing 1 methyl leads to weak agonist
What does this drug accomplish?
Methacholine (Amechol, Provocholine)
- Slightly more stable than ACh do to beta methy group
- More selective to muscarinic
- Muscarinic agonist
Describe the racemic methacholine?
- S+ enantiomer is the most active
- R- enantiomer is 20 fold less potent
- S+ isomer has slow metabolism than ACh
- R- isomer is not hydrolyzed by AChE, weak competitive inhibitor of enzyme
What does this drug accomplish?
Carbachol (Doryl, Milostat)
- Potent agonist that is nonselective
- Slight indirect activity promoting ACh release and weak AChE activity
- Increased hydrolytic stability do to carbamate linkage achieving oral bioavailability
What is carbachol used for?
Topical for glaucoma and intraocular for miosis in surgery
What are the side effects of carbachol?
Coreal edema and decreased vision
What does this drug accomplish?
Bethanechol (Urecholine, Mictone)
- Potent muscarinic agonist
- Increased hydrolytic stability from b-methyl (gives bulk) and carbamate ester
What is the use for bethanechol?
- Stimulant of GI tract smooth muscle and urinary bladder
- For the relief of post-surgical urinary retention and abdominal distension
What are the side effects of bethanechol?
Low toxicity, no serious, but not caution for asthmatic patients
What does this drug accomplish?
Pilocarpine (Almocarpine, Pilogel)
- Unstable to alkali and bases
What is the use for Pilocarpine?
Glaucoma and xerostomia
What are the side effects of pilocarpine?
Copious sweating, salivation, gastric secretion
What is the therapeutic use for Cevimeline?
Oral capsule for the treatment of xerostamia associated with Sjögren’s syndrome
