Med Chem Lecture 12

Front 1

Free acetylcholine that is not bound to a receptor is hydrolyzed by what?

Back 1

acetylcholinesterase (AChE).

Front 2

how does acetylcholinesterase (AChE) interfere with this mechanism?

Back 2

These molecules interfere with the mechanism by which the action of acetylcholine is terminated (hydrolyzed).

Front 3

Rapid hydrolysis of acetylcholine by AChE is inhibited, and this leads to the increase in what? What does this result in?

Back 3

this increases the concentration of acetylcholine in the synapse, resulting in production of both muscarinic and nicotinic effects.

Front 4

The enzymatically controlled hydrolysis reaction parallels the two chemical mechanisms for hydrolysis of esters. What is this reaction known as?

Back 4

acidic and basic hydrolysis of an ester.

Front 5

Acetylcholinesterase Inhibitors are NOT what?

What do ace inhibitors work to modulate?

Back 5

Ace inhibitors

“ACE INHIBTORS” work to modulate Angiotensin Converting Enzyme

Front 6

Draw the acid-catalyzed hydrolysis of an ester.

Back 6

Front 7

Draw the base-catalyzed hydrolysis of an ester.

Back 7

Front 8

Acetylcholinesterase inhibitors are classified as what? Why are they classified like this?

Back 8

classified as indirect cholinomimetics, because their principle mechanism of action does not involve binding to cholinergic receptors.

Front 9

Acetylcholinesterase inhibitors are used therapeutically to improve what?

Back 9

improve muscle strength in myasthenia gravis (caused by circulating antibodies that block acetylcholine receptors at the neuromuscular junction).

Front 10

Acetylcholinesterase inhibitors are also used in what? What are they used to decrease? How is this done?

Back 10

They also are used in open-angle glaucoma to decrease intraocular pressure by stimulating contraction of the ciliary muscle and sphincter of the iris.

Front 11

Acetylcholinesterase inhibitors They are used extensively as what? What real world scenario is this used in?

Back 11

insecticides and are in military arsenals for use as chemical warfare agents.

Front 12

Acetylcholinesterase Inhibitors may be ______ or _____

Back 12

Reversible or Irreversible

Front 13

Reversible Acetylcholinesterase Inhibitors – Type 1

Inhibitor binds to what? Have greater affinity for what? What don't they do? What are they useful in treatment of?

Back 13

Inhibitor binds to AChE enzyme with greater affinity than acetylcholine, but doesn’t hydrolyze. Many of these are useful in the treatment of early stage Alzheimers disease

Front 14

What 2 drugs are useful in Alzheimers disease?

Back 14

Tacrine

Donepezil hydrochloride

Front 15

Reversible Acetylcholinesterase Inhibitors – Type 2

Inhibitors react with what? What does this form? It is more stable to hydrolysis than what? What is it still capable of?

Back 15

nhibitor reacts with serine hydroxyl functional group in acetylcholinesterase to form an carbamylatedenzyme, which is more stable to hydrolysis than the acetylated enzyme from normal enzyne function, but still capable of undergoing hydrolysis to regenerate enzyme.

Front 16

Regeneration of active AChE (with free serine hydroxyl group) by hydrolysis of the carbamylated enzyme is ____ ___ than hydrolysis of the acetylated enzyme during normal enzyme function.

Back 16

MUCH SLOWER

Front 17

Irreversible AChE Inhibitors form what? This is very resistant to what? What can this functional group age partially into? What can these agents permantely do to an enzyme?

Back 17

Irreversible AChE Inhibitors form a phosphate ester with the enzyme which is very resistant to hydrolysis. This phosphate ester can also “age” into a partially hydrolyzed phosphate which is even more stable. These agents can permanently deactivate an enzyme.

Front 18

Irreversible AChE Inhibitors have antidotes which are what? What do functional group do they contain?

Back 18

Irreversible AChE Inhibitors have antidotes which are nucleophiles that rapidly hydrolyze phosphate esters. They contain an oximefunctional group.

Front 19

Muscarinic antagonists are compounds that have high binding affinity for what? What don't they have?

Back 19

Muscarinic antagonists are compounds that have high binding affinity for muscarinic receptors but have no intrinsic activity.

Front 20

When the muscarinic antagonist bings to the receptor it is proposed that the receptor protein undergoes what? What does the antagonist binding to the receptor produce?

Back 20

When the antagonist binds to the receptor, it is proposed that the receptor protein undergoes a conformational perturbation that is different from that produced by an agonist. Therefore, antagonist binding to the receptor produces no response.

Front 21

Because they act as competitive (reversible) antagonists of acetylcholine, these compounds have pharmacological effects that are what?

Back 21

opposite those of muscarinic agonists.

Front 22

Responses of muscarinic antagonists include what 5 effects?

Back 22

decreased contractions of smooth muscle of the gastrointestinal and urinary tracts, dilation of the pupils, and reduced gastric, mucociliary, and salivary secretion.

Front 23

What is Atropine used for?

Back 23

Atropine sulfate has a number of clinical uses; two of the most common are treatment of bradycardia and as a preoperative agent to reduce secretions before surgery.

Front 24

Nicotinic antagonists are chemical compounds that bind to what?

Back 24

cholinergic nicotinic receptors.

Front 25

ll therapeutically useful nicotinic antagonists are ____ ______? How do they work with acetylcholine?

Back 25

are ompetitive antagonists; in other words, the effects are reversible with acetylcholine.

Front 26

There are two subclasses of nicotinic antagonist? How are they classified?

Back 26

antagonists—skeletal neuromuscular blocking agents and ganglionic blocking agents—classified according to the two populations of nicotinic receptors.

Front 27

skeletal neuromuscular blocking agents and ganglionic blocking agents are what kind of blocking agents? What are they primarily used for? What do they produce and facilitate?

Back 27

These compounds are neuromuscular blocking agents - used primarily as an adjunct to general anesthesia. They produce skeletal muscle relaxation and facilitate operative procedures such as abdominal surgery.

Front 28

What are 5 examples of Nicotinic Antagonists?

Back 28

Front 29

Adrenergic drugs act to modulate what?

Back 29

modulate adrenoceptors that normally are activated by the neurotransmitter norepinephrine (noradrenaline), or they may directly act on the neurons that release the neurotransmitter.

Front 30

In the 1940s, norepinephrine was identified as what?

Back 30

the true neurotransmitter at the terminus of the sympathetic nervous system

Front 31

Norepinephrine and epinephrine are members of a class of pharmacologically active substances known as What? Because they contain within their structure both what?

Back 31

known as catecholamines, because they contain within their structures both an amine and ortho-dihydroxybenzene, which is known by the common chemical name of catechol.

Front 32

Adrenergic receptors are divided into what classes? according to their responses to different what? Principally what 3 drugs?

Back 32

Adrenergic receptors are divided into α- and β-adrenoreceptorclasses according to their responses to different adrenergic receptor agonists, principally norepinephrine, epinephrine, and isoproterenol.

Front 33

α-adrenoceptors are stimulated by these agonists in the following descending order of potency:

Back 33

epinephrine > norepinephrine >isoproterenol.

Front 34

β-adrenoceptors are stimulated in the following descending order of potency:

Back 34

isoproterenol> epinephrine > norepinephrine.

Front 35

Norepinephrine Has limited clinical application because of what? What does this cause?

Back 35

because of the nonselective nature of its action, which causes both vasoconstriction and cardiac stimulation.

Front 36

Norepinephrine must by given how? Because why?

Back 36

It must be given intravenously, because it has no oral activity (poor oral bioavailability) as a result of its rapid metabolism by intestinal and liver enzymes, 3-O-glucuronidation/sulfation in the intestine, and low lipophilicity.

Front 37

What kind of metabolism dose it have? Whats the duration?

Back 37

Rapid metabolism limits its duration of action to only 1 or 2 minutes, even when given by infusion.

Front 38

Epinephrine, similar to norepinephrine, is used to treat what? Why? What does it stimulate?

Back 38

to treat hypotensive crises and, because of its greater β-activity, to stimulate the heart in cardiac arrest.

Front 39

The β2-activity of epinephrine leads to its administration how? what else is used in? What does it inhibit?

Back 39

The β2-activity of epinephrine leads to its administration intravenously and in inhalers to relieve bronchoconstriction in asthma and to application in inhibiting uterine contractions.

Front 40

A major innovation in drug development for the β-adrenergic antagonists was introduced when it was discovered that what could be inserted? What is it inserted in?

Back 40

that an oxymethylene bridge, OCH2, could be inserted into the structure of pronethalolto afford propranolol, the first clinically successful β-blocker.

Front 41

During clinical trials as an antianginal, propranolol was discovered to have what kind of properties?

Back 41

antihypertensive properties, and it has been widely employed for that purpose for decades

Front 42

What 2 purposes is propranolol used for?

Back 42

Propranolol rapidly became widely used for a variety of cardiac arrhythmias as well. In addition, because of its high lipophilicity and ability to penetrate the CNS, propranolol has found use in treating disorders of the CNS, such as anxiety.

Front 43

Therapeutically exploited serotonergic targets include what 3 components?

Back 43

postsynaptic receptors, reuptake mechanisms, and metabolism of 5-HT itself.

Front 44

Tryptophan depletion, by reducing or eliminating dietary tryptophan, can result in what? . Conversely, tryptophan “loading,” by increasing dietary tryptophan, can result in what?

Back 44

result in decreased 5-HT biosynthesis.

result in the overproduction of 5-HT.

Front 45

What is an example that effectively interfere with the oxidative deamination of 5-HT to increase synaptic concentrations of 5-HT.

Back 45

Monoamine oxidase (MAO) inhibitors

Front 46

5HT1D Selective Receptor Agonists – the “Triptans” for what?

Back 46

For Migrane

Front 47

What are the dominant species of serotonergic receptor in human cerebral blood vessels?

Back 47

5-HT1D receptors

Front 48

5-HT1D receptors are potent what? What kind of people are they contradicted in?

Back 48

They are potent vasoconstrictors and therefore contraindicated for people with cardiovascular problems.

Front 49

Selective Serotonin Reuptake Inhibitors (SSRIs)

The actions of a neurotransmitter are terminated by what 3 action?

Back 49

by diffusion away from the synapse, by enzymatic degradation, and by reuptake into the presynaptic terminal via selective transporters.

Front 50

Selective Serotonin Reuptake Inhibitors (SSRIs)

Following reuptake, once the neurotransmitter is inside the neuron, it can be what? The reuptake process involves what?

Back 50

It can be re-stored in storage vesicles or metabolized. The reuptake process involves a high-affinity transporter protein that is localized in the presynaptic terminal membrane.

Front 51

Selective Serotonin Reuptake Inhibitors (SSRIs) areagents that block what?

What are they useful in?

Back 51

block the transporter and increase synaptic levels of 5-HT.

These are useful for the treatment of depression, obsessive-compulsive behavior, and panic disorders.

Front 52

The ergot alkaloids exhibit affinity for what 3 receptor systems?

Back 52

for α-adrenergic, dopaminergic, and serotonergic receptor system.