1.4 Cholinergic Med Chem

El Sayed

what are the two types of cholinergic receptors

muscarinic and nicotinic

where are most of the cholinergic receptors located in the body

PNS

are nicotinic receptors inhibitory or excitatory

excitatory

what are the muscarinic receptor subtypes

M1, M2, M3, M4, M5

which muscarinic receptors are excitatory

M1, M3, M5

which muscarinic receptors are inhibitory

M2 and M4

are nicotinic receptors GPCRs or ligand gated?

ligand gated

how many transmembrane domains does a nicotinic receptor have

5

which nicotinic transmembrane domain is responsible for opening and closing in response to ACh

TM2

is the neurotransmitter binding region of nicotinic receptors intracellular or extracellular

extracellular

how many transmembrane domains do muscarinic receptors have

7

are muscarinic receptors GPCRs or ligand gated?

GPCRs

which transmembrane domain of muscarinic receptors is responsible for binding to ACh

TM3

why is TM3 of muscarinic receptors responsible for binding to ACh

it has Asp 105 in it which acts as an anionic group to directly bind to the quaternary ammonium on the ACh

cholinergic neurons release ____

ACh

cholinergic receptors respond to _____

ACh

cholinergic ____ release ACh and cholinergic ____ respond to ACh

neurons, receptors

muscarinic agonists are also called

parasympathomimetics

what are some acetylcholine like structures

methacholine, carbachol, and bethanechol

what has a non-acetylcholine like structure

pilocarpine

AChE (acetylcholinesterase) is responsible for…

hydrolysis of ACh to form acetate and choline

what controls the action of ACh

AChE

ACh that is not bound to receptors is ______ which terminates its action

hydrolyzed by AChE

if AChE were inhibited it would lead to…

increased ACh concentration and prolong its actions on neurons

inhibition of AChE can be useful for which diseases

myasthenia gravis, glaucoma, alzheimers

AChE has an ____ site that can bind to the charged choline of ACh

anionic

active esteratic site contains a ___residue that is involved in the hydrolysis of the ester bond

nucleophilic serine

how does ACh get metabolized

the nucleophilic serine hydroxy group attacks the ester carbonyl group of ACh which forms a tetrahedral intermediate, which breaks down resulting in a release of choline intermediate acetylated serine which hydrolyses to release ACH E and acetic acid

why cant ACh be used as a drug

no selectivity between receptors

poorly absorbed

hydrolyzed in gut (inactivated)

not orally active

True or false:

ACh is selective for nicotinic receptors

false

why is ACh poorly absorbed thru cell membranes

contains a quaternary ammonium salt

why is ACh not orally active

hydrolysis in the gut

why does ACh undergo rapid enzymatic hydrolysis in the blood and tissues

because of its ester group

does ACh have any chiral centers

nah fam

the torsion angle of ACh is between which areas

ester oxygen atom and quaternary nitrogen

which structure of ACh is the most common and active

synclinal

which conformation of ACTM was more potent for muscarinic receptors

trans-ACTM

compounds that have a positive charge on the atom in place of the N on ACh are _____

active

removal of a methyl group on ACh causes…

decreased activity

removal of a ____ on ACh leads to decreased activity

methyl

there should be no more than ___ atoms between N and the terminal hydrogen atom for maximal muscarinic potency

5

there should be no more than 5 atoms between N and the terminal hydrogen atom for maximal ____ potency

muscarinic

replacing the nitrogen on ACh with which 4 atoms leads to less activity than ACh

S, As, P, and Se

if ACh’s methyl group was replaced with larger and bulkier groups then it was ____

inactive

when three methyl groups were replaced by _____ it formed a cholinergic antagonist

ethyl

when three methyl groups were replaced with ethyl groups instead it formed…

cholinergic antagonists

successive removal of methyl groups and replacement with hydrogen makes them…

primary, secondary, and tertiary amines with decreasing muscarinic activity

Acetic acid esters of quaternary ammonium alcohols of greater length than choline led to a series of compounds with rapid ____ in activity

decreases

Acetic acid esters of quaternary ammonium alcohols of ____ length than choline led to a series of compounds with rapid decrease in activity

greater

ing rule of 5

There should not be more than 5 atoms between the N & terminal H atom for maximal muscarinic potency

Ethylene bridge replaced by alkyl groups _____ than methyl led to less active compounds with agonist activity 1/10 as active as ACh

larger

Ethylene bridge replaced by alkyl groups larger than methyl led to _____ active compounds

less

Addition of a methyl group on β-carbon to quaternary nitrogen atom led to a compound with activity similar to AcCh, but more selective to ______ receptors

muscarinic

Addition of a methyl group on ____-carbon to quaternary nitrogen atom led to a compound with activity similar to AcCh, but more selective to muscarinic receptors

beta

would this structure be more selective for nicotinic or muscarinic receptors?

muscarinic

Addition of methyl group on α-carbon to quaternary N atom led to compound with slightly less activity than AcCh, but more selective to ______ receptors

nicotinic

Addition of methyl group on ____ carbon to quaternary N atom led to compound with slightly less activity than AcCh, but more selective to nicotinic receptors

alpha

would this structure be more selective for muscarinic or nicotinic receptors?

nicotinic

When acetyl group were replaced with higher homologues (propionyl, butyryl) activity was ____ vs ACh

decreased

Choline esters of aromatic acids or higher molecular weight acids possess cholinergic _____ activity.

antagonist

In acetylcholine, ____ group is susceptible for hydrolysis.

acetyloxy

In acetylcholine, acetyloxy group is susceptible for ____.

hydrolysis

carbachol and bethanechol are both ____ active

orally

Modifications of carbachol resulted in ____

bethanechol

Modifications of ____ resulted in bethanechol

carbachol

Bethanechol is orally available potent ______ agonist

muscarine

Bethanechol is orally available potent muscarinic ______

agonist

Bethanechol has almost no activity on ____ receptors

nicotinic

which enantiomer of bethanechol has greater binding affinity for muscarine receptors than the other

S

where are the three chiral centers on muscarine

to be a muscarinic agonist, the molecule must have a quaternary N with a ______

positive charge

to be a muscarinic agonist, the molecule must have a ____ with a positive charge

quaternary N

to be a muscarinic agonist, the size of the alkyl groups on the N should NOT excess the size of a ______

methyl group

to be a muscarinic agonist, there should be an ____ atom preferably…

oxygen; ester-like and participating in a hydrogen bond

to be a muscarinic agonist there should be ____ carbons between the oxygen and nitrogen

2

examples of muscarinic agonists

methacholine, carbachol, bethanechol, pilocarpine, donepezil

B

C

C

pilocarpine has high affinity for ____ receptors

muscarinic

how many chiral centers does pilocarpine have

2

due to pilocarpines lactone group, it undergoes ____ to the inactive pilocarpic acid

hydrolysis

pilocarpine is hydrolyzed to the inactive…

pilocarpic acid

is pilocarpic acid active or inactive

inactive

due to pilocarpines lactone group, base catalyzed epimerization occurs to make _____ which is inactive

isopilocarpine

due to pilocarpines lactone group, ______ occurs to make isopilocarpine which is inactive

base catalyzed epimerization

pilocarpine has issues with…

drug storage and shelf life

AChE inhibitors lead to…

increases the concentration of acetylcholine in the synapse, inducing both muscarinic & nicotinic effects.

classes of physostigmine

AChE inhibitor AND a muscarinic agonist

physostigmine is used to treat

glaucoma and antimuscarinic poisoning

which N of Physostigmine is most basic

physostigmine is protonated at physiological pH so it can…

bind to the anionic site of AChE

the ____ residue of AChE can attack physostigmine carbamate group & serine OH is carbamoylated

serine

physostigmine inhibition of AChE is an example of

slowly-reversible inhibition (pseudo-irreversible inhibition)

what occurs in slowly-reversible inhibition (pseudo-irreversible inhibition) of AChE via physostigmine

involving covalent bond formation & slow cleavage

When ______ such as physostigmine bind to AChE, hydrolysis of carbamate occurs forming a carbamoylated enzyme

aryl carbamates

The rate of hydrolysis of carbamoylated enzyme is much _____ than hydrolysis of acetylated enzyme

slower

compounds that reversibly bind AChE & slow its AChE hydrolytic reaction can act as _____

AChE reversible inhibitors

which has better AChE binding, alkyl carbamates or aryl carbamates?

aryl carbamates

B