ACH

Question 1

how does ACH work?

Answer 1

• The release of ACH into the cyapse- agonist would work here against cholinergic receptor
• Once no longer needed enzyme group cleaves off the acetyle group to release choline – can be recycled

Question 2

what is ACH synthesized from?

Answer 2

• It is made from coenzyme A ester and choline

Question 3

what kind of reaction is the synthesis of ACH?

Answer 3

• Choline has rel neuclophilic reaction- transesterification rxn- choline

Question 4

Why not use acetylcholine as a cholinergic receptor agonist?

Answer 4

• Hydrolysis in the stomach, if administered orally.
• Esterase hydrolysis in blood.
• Selectivity issues

Question 5

where are nicotine and muscarine active?

Answer 5

Nicotine active at synapses between nerves and also between nerves and skeletal muscle.
Muscarine active at synapses between nerves and smooth muscle / cardiac muscle.

Question 6

what is the difference between nicotine and muscarine?

Answer 6

Nicotine (tobacco) and muscarine (poisonous mushroom) are both agonists, but produce differing biological responses

Question 7

how does the muscarinic receptor bind?

Answer 7

+ve charge and ester essential. Charge – ester distance is important (selectivity, see later).
•Very little scope for extension, tight in pocket.
•Potential cation-p interaction

Question 8

what makes an ACH analogue unstable

Answer 8

an ester group- prone to hydrolysis

Methyl group in methacholine breaks this up.

Question 9

how do you stablise ach?

Answer 9

Carbamates (urethanes) intrinsically more stable to hydrolysis.
- Change the terminal group of the ester to nh2- uraphin- amide like character- tend to protect from carbophilic attack

Question 10

what are the job of ACH?

Answer 10

Prevents acetylcholine breakdown.

•Indirectly increases ACh concentration.

Question 11

how does ACHE work?

Answer 11

• Enzyme is anchored into cell membrane with triple stranded collagen ‘tree-like’ structure.
• Enzyme has four sub-units, each with one active site.
• Disulphide bridges key to maintaining overall structure.

Question 12

what is a natural product with anticholinesterase activity?

Answer 12

Physostigmine, Sometimes called eserine, product of poisonous calabar bean

Question 13

what is physostigmine mechanism of action & SAR?

Answer 13

• Carbamate required.
• Benzene important (phenoxide leaving group).
• Ionizable nitrogen is important.

Question 14

what are the rpoperties of Physostigmine analogues?

Answer 14

•High toxicity of physostigmine has lead to development of safer analogues.
•Miotine better, but free base form can cross BBB, leading to CNS effects
.•Permanent charge on Neostigmine and Pyridostigmine prevent BBB passage.
•Extra methyl groups sterically protect carbonyl from attack by water once bound to AChE. Increases duration of action

Question 15

how does ACHE inhibitors work for alzhimers?

Answer 15

• ACh acts in CNS as well as periphery.
• Drugs not quaternised in order to pass BBB.
• GI side-effects from lack of specificity.

Question 16

what is the role of Antagonists: Muscarinic?

Answer 16

•Reduction of gastric secretions and saliva.
•Reduction of GIT and urinary tract motility.
•Opthalmic use: dilatation of pupils
•Treatment for peptic ulcers.
•Treatment for Parkinson’s Disease
.•Treatment for motion sickness.

Question 17

what was Atropine used for?-natrual product

Answer 17

Used for pupil dilation (ancient), reduction of GI motility and as treatment for anticholinesterase poisoning

Question 18

what was Hyoscine (scopolamine) used for?

Answer 18

used for motion sickness obtained from thorn apple (Datura stramonium).

Question 19

how do Atropine vs ACh compare?

Answer 19

•Retains ester and amine (protonated) at required distance
.•Free base able to cross BBB, causes hallucinations at high doses. Used in witchcraft.
•Antagonism due to extra binding groups, can interact with receptor without inducing conformational change associated with signal transduction.

Question 20

why do we use analogues?

Answer 20

to reduce CNS s/e:
Quaternised salts can not pass BBB.
•Ipratropium is a SAMA, and used clinically as a bronchodilator.
•Atropine methonitrate used to lower GIT motility.
•Amprotropine is active: rigidity not required

Question 21

what do Large branched ester substituents promote?

Answer 21

promote antagonist behaviour.

Question 22

what is the ideal receptor for COPD?

Answer 22

muscarninic 3

Question 23

what is the snap lock mechanism?

Answer 23

• Goes in normal sort of way- 4 aromatic residues which form aromatic box- locks molecule in- and cant get back out- has to cause another rearrangement before it can slide out

Question 24

what ar Nicotinic antagonists used for?

Answer 24

neuromuscular blocking agents
Lower doses of active ingredient tubocurarine used to relax abdominal muscles pre-surgery.
•Allows for lower doses of anaesthetic to be used.

Question 25

how does Tubocurarine and the cholinergic receptor bind?

Answer 25

Early theories suggested binding to two separate ACh sites, but this does not fit modern structural data.
•Current model involves one site and a cysteine residue.

Question 26

what are Other nicotinic cholinergic antagonists?

Answer 26

Just about any molecule with two cations held roughly 1.15 nm apart!
•Two ionic charges overcome lack of ester unit of ACh.
•Main issue is selectivity,

Question 27

what are self-destructing drugs?

Answer 27

In blood undergoes Hofmann elimination.