Neuro Exam 1_Cholinergics MedChem

1. alpha

2. beta

what are the subtypes of cholinergic receptors

asthma

M3 antagonists can be used to treat ____

ligand-gated ion channels

nicotinic ACh receptors are ___(ligand gated ion/G protein coupled)

5 transmembrane domains.

TM2 is the component of the domains that is responsible for opening and closing the channel upon binding/unbinding of ACh

describe the structure of nicotinic ACh receptors

cholinergic

neurons that release acetylcholine

cholinergic receptors

receptors that respond to acetylcholine

nicotinic

acetylcholine receptors that are particularly responsive to nicotine

muscarinic

acetylcholine receptors that are particularly responsive to muscarine

a single monomeric protein that spans the cell membrane seven times

explain the structure of muscarinic receptors

Aspartic acid (Asp)

amino acid

component of nicotinic and muscarinic receptors necessary for binding of a ligand

carboxy of aspartic acid forms ionic interactions with quaternary amine of ACh

carboxy

functionality if aspartic acid that forms ionic bonds with muscarinic and nicotinic receptors

required for binding to receptors

parasympathomimetics

Drugs that mimic the parasympathetic nervous system

also referred to as cholinergic agonist drugs.

yes

are muscarinic agonists parasympathomimetics

acetylcholine

S-nicotine

muscarine

1. methacholine (beta-methylcholine)

2. carbachol

3 bethanechol

4. acetylcholine

what are acetylcholine-like structures that can activate nicotinic and muscarinic receptors

pilocarpine

what are non-acetylcholine like structures that can activate nicotinic and muscarinic receptors

AChE (acetylecholine enzyme)

enzyme that catalyzes the hydrolysis of the neurotransmitter acetylcholine to acetate and choline

inactivates ACh

controls the action of acetylcholine

AChE

what controls the action of acetylcholine

increased acetylcholine concentrations and prolonged action on the nuerons

what would AChE inhibition result in

3*10^8 molecules/second

speed at which AChE can hydrolyze ACh

summary cleaves the ester bond to form acetate and choline

1. AChE anionic site binds to the positively charged quaternary ammonium of acetylcholine

2.esteratic site that contains a serine residue performs hydrolysis of the ester bond. A tetrahedral intermediate is formed on the ester carbonyl group of acetylcholine

3. choline is released

4. acetylated serine is hydrolyzed and acetate is released

describe the activity of AChE, include info about the active site of AChE

1. it is not selective for muscarinic vs nicotinic

2. poorly absorbed through cell membranes/GI tract bc of the quaternary ammonium salt. (summary poor bioavailability)

3. metabolized rapidly (ester functional group is hydrolyzed in the gut, skin, blood and most tissues)

why can acetylcholine not be used as a drug

false

the stereochemistry of ACh determines activity.

T/F all confirmations of ACh are equivalent in activity

rotation occurs on the bond between the alpha and beta carbon

note: other bonds in the molecule can rotate but that alpha-beta carbon bond is the most significant

what bond of acetylcholine is responsible for the conformation changes

synclinal/gauche/trans

it is the most stable with the lowest energetic state.

what is the most common/preferred confirmation of ACh

trans-ACTM

note: it is more predominant bc it is more stable. cis-ACTM has higher energy

is the cis-ACTM or trans-ACTM more potent at muscarinic receptors?

true

T/F while designing cholinergic ligands, chirality and stereochemistry is important

1. quarternary ammonium group: responsible for ionic binding to Asp of receptors

2. oxygens and nitrogens: take part in hydrogen bonding, which is needed for receptor interactions

3. Ing's rule: there should not be more than 5 atoms between the N and terminal H atom for maximal muscarinic potency

explain the important structural characteristics of acetylcholine that play a role in its activity

removal of methyls: decrease of activity

addition of bulkier groups: loss of activity

specific replacement with ethyl groups: becomes antaognist

what would happen to the activity of acetylcholine if the methyl groups attached to the nitrogen were subsequently removed or replaced with a bulkier group

decreased activity

what would happen to the activity of acetylcholine if the nitrogen was replaced (with S, As, P, or Se)

Ing's rule

no more than 5 atoms between the nitrogen and the terminal hydrogen atom

what is required for ACh and similar molecules to have the maximum muscarinic potency

muscarinic selectivity: addition of methyl group on the beta carbon to nitrogen

nicotinic selectivity: addition of methyl group on alpha carbon to nitrogen

how to make acetylcholine more selective for muscarinic or nicotinic receptors

changes in oral stability and activity

what can modification of the acyloxy group of ACh result in

acyloxy

cholinergic antagonist

choline esters of aromatic acids or higher molecular weight acids possess ___ activity

decreased activity

what does replacement of the acetyl group of ACh with higher homologues (propionyl, butyryl) result in

carbamic acid ester

replacement of carbon 5 with a nitrogen. creates carbachol

modification of the acyloxy group of ACh that results in a more stable molecule with better oral availability

carbachol

modified ACh. Nitrogen replaced carbon 5

bethanechol

modified carbachol

methyl group on beta carbon to the quaternary nitrogen

has better stability and oral bioavailability due to nitrogen in place of carbon 5. AND the methyl group on the beta carbon provides muscarinic selectivity and provides steric hinderance to make molecule more resistant to hydrolysis

bethanechol

an orally available potent muscarine agonist with almost no nicotinic acitivity

yes

S (counterclockwise rotation) enantiomer has greater binding affinity for muscarine receptors than R (clockwise rotation) enantiomer

note: beta carbon to nitrogen is the chiral center

do the enantiomers of bethanechol have varying activity

muscarine

substance obtained from the red mushroom

has cholinergic agonist activity

has three chiral centers

3

note: the alpha carbons and beta carbon to the oxygen

how many chiral centers does muscarine have

1. posses a quaternary nitrogen atom with a positive charge

2. size of alkyl groups substituted on the nitrogen must not exceed the size of a methyl group

3. contain an oxygen atom, preferably in the form of an ester, to participate in hydrogen bonding

4. there is a two carbon unit linker between the oxygen and nitrogen

rules for designing a muscarinic (and nicotinic) agonist

1. presence of methyl group on alpha or beta carbon to the nitrogen to create stability

2. replacement of carbon 5 with a nitrogen

note: these modifications slow hydrolysis

modifications to ACh that can slow down its metabolism by AChE

R

enantiomer of bethanicol that is weaker in activity but is hydrolyzed slower

pilocarpine

muscarinic agonist

imidazole alkaloid from the plant pilocarpus jaborandi

has stability problems due to stability

1. hydrolysis of lactone

2. epimerization

note. this occurs rapidly so pilocarpine has stability issues and a short shelf life

how is pilocarpine metabolized/inactivated

AChE inhibitors

substances that interfere with the mechanism by which the action of ACh is terminated

cause increased concentrations of ACh at the synapse

physostigmine

AChE inhibitor

a natural alkaloid with a carbamate moiety which remembers the ester linkage of acetylcholine

1. ester forms a tetrahedral intermediate with the serine of AChE (carbamoylated enzyme)

2. slow hydrolysis of the intermediate results in physostigmine's antagonistic effects

this is considered slowly reversible inhibition (aka pseudo-irreversible inhibition) due to the covalent bond formation of the tetrahedral intermediate and its slow cleavage

describe the mechanism of AChE inhibition by phsostigmine

physostigmine

does physostigmine or acetylcholine have a higher affinity for AChE

false

physostigmine is a tertiary amine so it does not have a positive charge

T/F it is the positive charge of physostigmine that allows it to bind to AChE

it is more lipophilic and can cross the BBB

what is the advantage of physostigmine being a tertiary amine without a positive charge instead of a quaternary ammonium salt

1. esterases hydrolyze the carbamate ester to eseroline (which is an inactive metabolite bc it lose the carbamate)

2. eseroline is oxidized to rubreserine (no carbamate so inactive)

how is physostigmine metabolized

noestigmine

AChE inhibitor that has a substituted carbamate group, benzene ring, and quaternary ammonium

formulated as a salt

has low CNS/BBB penetration bc it is hydrophilic due to the quaternary ammonium

cholineesterases in the liver and skeletal muscle

how is neostigmine metabolized

no

it be polar

can this molecule (pyridostigmine) cross the BBB

pyridostigmine

AChE inhibitor

closely related to neostigmine

incorporated a charged nitrogen into the pyridine ring

is orally effective and has longer half life than neostigmine

carbamate ester is cleaved by esterases

how is pyridostigmine metabolized

edrophonium chloride

a reversible acetylcholinesterase inhibitor

competitively inhibits AChE at the neuromuscular junction

used to treat myasthenia gravis to prolong ACh presence in the synaptic cleft

myasthenia gravis

condition in which the body produces autoantibodies which block, inhibit or destroy nicotinic ACh receptors in the neuromuscular junction

false

it is not a carbamate ester so it does not carbamoylate AChE

T/F edrophonium carbamoylates AChE

insecticidies

what are irreversible inhibitors of AChE used as

prefer reversible inhibition bc irreversible is toxic

irreversible AChE inhibitors cannot be used as medications

are reversible or irreversible AChE inhibitors preferred for medication development

muscarinic antagonists/anticholinergic

substances that bind mAChRs and cause conformational changes that result in no response being produced

parasympatholytics

Drugs that reduce the activity of the parasympathetic nervous system

also called anticholinergics.

amine group separated by a distance to ester functional group

atropine is usually used

base of muscarinic antagonists

increase potency as mAChRs antagonists

substitution of lipophilic rings on the carbonyl carbon of the ester moiety...

yes

does atropine follow Ing's rule of 5 (which is necessary for cholinergic binding)

substituents at R1 and R2 should be carboxcylic or heterocyclic for max activity

**napthalene type rings will decrease activity

R3 substitution can be H, OH, CH2OH, or CONH2

** substitution must be able to participate in hydrogen bonding

X substitution is best if it is an ester, but presence of an ester is not necessary for activity

N substituent can be a quaternary ammonium salt but it’s not necessary

distance between N and substituted C is usually 2-3 Cs

using the base of mAChR antagonists that is pictured, explain the basic structure and relationship

competitive antagonists

means they must compete with agonists for binding

what type of antagonists are muscarinic antagonists

oxybutinin

muscarinic antagonist

used to relieve urinary and bladder difficulties, including frequent urination and inability to control urination, by reducing muscle spasms

M1-M3

what subtypes of muscarinic receptors does oxybutinin antagnoize

M3

antimuscarinic drugs that maintain bronchiole tone

used in combination with B2 agonists to treat asthma

nicotinic antagonists

nueromuscular blocking agents

chemical compounds that bind to AChR but have no efficacy

1. skeletal neuromuscular blocking agents

2. ganglionic blocking agents

types of nAChR antagonists

tubocurarine

nAChR antagonist

toxic alkaloid derived from the bark of the chondrodendron tometosum plant; known for its use as an arrow poison

a depolarizing neuromuscular blocing agent

decamethonium

first synthesized neuromuscular blocking agent

10-12 unsubstituted Ch2 are optimum for activity

10-12

ideal number of carbons between the nitrogens of decamethonium for optimal activity

succinylcholine chloride

anticholinergic

dimer of acetylcholine bonded through an alpha carbon of each ACh

is rapidly hydrolyzed and is used for rapid induction of neuromuscular blockage

non-depolarizing neuromuscular blocking agents

anticholinergics

agents that have one or two quaternary ammonium groups

the protonated tertiary amine is converted to a quaternary ammonium group in vivo

what happens to non-depolarizing neuromuscular blocking agents that only have one quaternary ammonium group and a protonated tertiary amine like the one pictured

activity differences:

d-tubocurarine: formulations contain bisulfites and can create allergic reactions in patients with bisulfite allergy

metocurine: has two quaternary amines instead of one. formulated as an iodide salt so allergy issue is gone. significantly more potent than d-tubocurarine with a longer duration of action

structure differences:

d-tubocurarine: one quaternary amin and one tertiary amine

metocurine: two quaternary amines. the hydroxyl groups are changed to methyl esthers

difference between d-tubocurarine and metocurine

atracurium besylate

a tetrahydroisoquinoline based neuromuscular blocking agent

nondepolarizing neuromuscular blocker

consists of 2 quaternary ammonium groups located on two substituted tetrahydroisoquinolines with an aliphatic diester connection

1. hydrolysis of the ester groups

2. MAIN PATHWAY non-enzymatic base-ctalyzed reactions (Hoffmann elimination)

metabolism results in formation of laudanosine (an inactive compound)

explain the metabolism of atracurium besylate

false

it is not metabolized in the liver. Its esters are hydrolyzed and it undergoes Hofmann eliminiation

T/F atracurium besylate is metabolized in the liver

hoffman elimination

aka exhaustive methylation

process where a quaternary amine is reacted to create a tertiary amine and an akene by treatment with excess methyl iodide followed by treatment with silver oxide, water, and heat

temperature and pH

note: increased body pH increases elimination where as decreased temperature decreases elimination

what is hofmann elimination dependent upon

false

hofmann elimination is dependent upon temperature and pH. it is NOT dependent on plasma esterase activity, obesity, age, or status of renal/hepatic function

T/F Hoffman ELIMINATION of atracurium is affected by the level of plasma esterase activity, obesity, age, and the status of renal/hepatic function

true

T/F EXCRETION of atracurium and its metabolite laudanosine is dependent on hepatic and renal functions

mivacurium chloride and doxacurium chloride

anticholinergic

a short duration non depolarizing neuromuscular blocking drug

cis-cis

note: trans-trans and cis-trans

which conformation of the diesters of mivacurium chloride has the lowest potency

pancuronium

steroid based neuromuscular blocking agent

has a mix of active and inactive metabolites

increases blood pressure and heart ratev

vecuronium bromide

steroid based neuromuscular blocking agent

all of its metabolites are active so it has prolonged neuromuscular action

does not induce histamine so it has no CV side effects

pipecuronium bromide

steroid based neuromuscular blocking agents

excreted unchanged and has minimal cardiovascular side effects

rocuronium bromide

steroid based neuromuscular blocking agent

intermediate acting neuromuscular agent that does not induce release of histamine

pancruonium: has two quaternary ammoniums and induces histamine to cause side effects of increased blood pressure and heart rate

vecuronium bromide: only has one quaternary ammonium. the tertiary nitrogen is converted to a quaternary ammonium in vivo. it does not induce histamine so it has no CV side effects

pancuronium vs vercuronium bromide. what is the difference