Med Chem Lecture 11

Front 1

Describe antisense therapy for mRNA interference

Back 1

Front 2

When does Rnase H cleave RNA?

Back 2

When initiated by oglionucleotide

Front 3

Ribonuclease (commonly abbreviated RNase) is a type of nuclease (nuclease = enzyme that cleaves phosphodiester bonds) that catalyzes what?

Back 3

the degradation of RNA into smaller components

Front 4

During normal DNA replication, RNase H is responsible for removing what? This allows for what?

Back 4

the RNA primer, allowing completion of the newly synthesized DNA.

Front 5

Rnase has what kind of mechanism?

Back 5

Rnase has a hydrolytic mechanism. It has a classification EC 3.1.26.4

Front 6

What is transcription?

Back 6

Transcription – antisense oligonucleotide initiates degradation of mRNA strand

Front 7

What is Capping?

Back 7

antisense oligonucleotide prevents further expression of RNA into protein

Front 8

What is splicing and translation?

Back 8

antisense oligonucleotide prevents further splicing and blocks translation

Front 9

The siRNAs are generated from what?

The siRNA is then incorporated into what? What does it guided? What happens from there?

Back 9

ong, double-stranded RNA molecules processed by an enzyme called "Dicer”

into RNA-induced silencing complex (RISC), which guides a nuclease (Rnase H) to the target mRNA, which is subsequently degraded, thus blocking protein synthesis.

Front 10

The structure of siRNA consists of what strands and what nucleotides? What is essential for RISC docking?

Back 10

Two strands designated “guide” and “nonguide”

Two nucleotide 3’ “overhangs” and 5’ phosphates present

5’ phosphorylation essential for RISC docking

Front 11

What 4 things do conventional drug targets?

Back 11

1) gene regulation; alter mRNA expression (e.g. fibrates, glitazones) inside nucleus.
2) Inhibit protein synthesis (some antibiotics).
3) Alter post translational protein processing.
4) Direct agonist or antagonist with a specific protein.

Front 12

What are two steps insiRNA therapy?

Back 12

1) siRNA mediated cleavage of mRNA
2) Degradation of the mRNA fragments

Front 13

siRNA mediates selective cleavage of what? Specificty is determine by what?

Back 13

siRNA mediates selective cleavage of specific mRNA
Knock-down of a specific protein
Specificity is determined by siRNA sequence.

Front 14

What Improves Stabilityof Oligonucleotides?

Back 14

Backbone modifications

Front 15

What are 4 first generation backbone modifications?

Back 15

Front 16

What are second generation backbone modifications?

Back 16

Front 17

What is the first marketed antisense therapeutic agent (cytomegalovirus inhibitor?

Back 17

Fomivirsen

Front 18

What are 3 Various Delivery Technologies that Can Potentially be Used for siRNA Delivery?

Back 18

Naked siRNA(with or without targeting agentslike cholesterol)

Stable Nucleic Acid–Lipid Particles (SNALPs)

Lipid Nano Particles (LNPs)

Front 19

What are 4 subcategories (type of neurotransmitter)

Back 19

1. Cholinergic (acetylcholine)
2. Adrenergic (noradrenaline/norepinephrine)
3. Serotinergic (serotonin)
4. Amino Acid

Front 20

Nervous System = ?
Central Nervous System =?
Peripheral Nervous System=?

Back 20

Nervous System = CNS (Central) + PNS (Peripheral)

Central Nervous System = Brain and Spinal Chord

Peripheral Nervous System = sensory neurons (informs CNS of stimulus) + motor neurons (“effectors” running to muscles and glands that take action)

Front 21

The PNS is divided into what two components?

Back 21

The PNS is divided into somatic and autonomic components.

Front 22

Somatic Nervous System gives us what? It has what to react to external stimulus? How many pairs of cranial nerves and spinal nerves? All of the spinal nerves are what?

Back 22

gives us conscious awareness of the external environment
also has the motor neurons to react external stimulus
has 12 pairs of cranial and 31 pairs of spinal nerves
all of the spinal nerves are mixed sensory/motor neurons

Front 23

In Autonomic Nervous System What neurons that run from the CNS to major organs in the body?

Back 23

Sensory and motor

Front 24

In ANS What two sets of motor neurons are present?

Back 24

preganglionic arise in the CNS and run to a ganglion, where they synapse with the postganglionic neurons that run to the effectororgan

Front 25

What are 2 subdivisions of ANS?

Back 25

sympathetic and parasympathetic

Front 26

In Sympathetic Nervous System preganglionic neurons arise where? and go to where?

Back 26

in spinal chord and go to sympathetic ganglia on each side of the spinal chord

Front 27

In the Sympathetic Nervous System what 3 things may neurons do?

Back 27

the neuron may 1.) connect with postganglionic neurons 2.) run up or down sympathetic chain and synapse higher or lower in the body or 3.) leave the ganglion to a special ganglion synapse in the viscera or connect directly to the highly specialized secretory portion of the adrenal medulla

Front 28

In the Sympathetic Nervous System the neurotransmitter released by the preganglionic neurons is what?

Back 28

is acetylcholine

Front 29

In the Sympathetic Nervous System the neurotransmitter released by the postganglionic neurons is what?

Back 29

noradrenaline (also called norepinephrine)

Front 30

noradrenaline may be what to particular gland or muscle?

Back 30

excitatory or inhibitory

Front 31

stimulation of the sympathetic branch of the of the autonomic nervous system id responsible for what reflex?

Back 31

fight or flight

Front 32

the release of adrenalin from the adrenal medulla ensures what?

Back 32

that all cells of the body will be exposed to sympathetic stimulation even when no postganglionic neurons reach them directly

Front 33

In the Parasympathetic Nervous System, what is the main nerve? where is it originated from?

Back 33

the main nerves are the vagus nerves, originating in the medulla oblongata

Front 34

In the Parasympathetic Nervous, each preganglionic parasympathetic neuron synapses with what? Where are they located?

Back 34

just a few postganglionic neurons which are located near or in the effector organ/muscle/gland

Front 35

In the Parasympathetic Nervous what is the neurotransmitter for the pre-and most of the post-ganglionic neurons? Some postsynaptic neurons release what?

Back 35

acetylcholine

Some postsynaptic neurons release nitric oxide as their neurotransmitter

Front 36

the parasympathetic system reverses what?

Back 36

reversing the physiologic effects of “fight or flight”

Front 37

In Parasympathetic Nervous System the vagus nerve releases what? Why?

Back 37

the vagus nerve reverses inflammation also, since acetylcholine suppresses the release of inflammatory cytokines in inflamed tissues

Front 38

Cholinergic means what?

Back 38

Neurons that Release Acetylcholine

Front 39

Cholinergic is further subdivided into what? depending on their ability to what?

Back 39

into muscarinic and nicotinic depending on their ability to bind the naturally occurring alkaloid muscarine or nicotine

Front 40

chemical compounds that cause stimulation of the parasympathetic nervous system are called what?

Back 40

cholinomimetic or, more specifically, parasympathomimetic agents.

Front 41

cholinomimetic agents might be agonists that act directly on what? They might function as what?

Back 41

on cholinergic receptors or function as inhibitors of acetylcholinesterase (AChE), the enzyme responsible for hydrolysis of acetylcholine

Front 42

acetylcholine is widespread in what system?

Back 42

autonomic nervous system, and imbalanced parasympathetic tone has serious physiological consequences

Front 43

many synthetic cholinergic agonists have been designed using what?

Back 43

structure–activity relationships (SARs) based on the structure of acetylcholine

Front 44

What are Muscarinic Receptors subtypes? What kind of receptors are they?

Back 44

subtypes designated M1-M5 and high subtype selectivity is rare.
g -protein coupled receptors

Front 45

Nicotinic Receptors are found at what 3 sites? What are they classified as? What does the receptor create? what does this modulate?

Back 45

found at skeletal neuromuscular junction, adrenal medulla and autonomic ganglia
classified as ligand-gated ion channel receptors
the receptor creates a transmembrane ion channel which modulates the flow of ions – primarily Na+ and K+ - in and out of the cell membrane

Front 46

The nicotinic receptor of muscle tissue is a transmembrane glycoprotein consisting of what four types of subunits

Back 46

subunits—α, β, γ(orε), and δ.

Front 47

Acetylcholine is biosynthesized in cholinergic neurons by what? What is the enzyme catalyzing this reaction? What happens to it?

Back 47

by the enzyme-catalyzed transfer of the acetyl group from acetyl coenzyme A (acetyl-S-CoA) to choline, a quaternary ammonium alcohol.
cholineacetyltransferase, is also biosynthesized in the cholinergic neuron.

Front 48

Acetylcholine in the synapse can bind with what? To produce what?

Back 48

with cholinergic receptors on the postsynaptic or presynaptic membranes to produce a response.

Front 49

What happens to a free acetylcholine that is not bound to a receptor? This hydrolysis is the physiologic mechanism for terminating what?

Back 49

is hydrolyzed by acetylcholinesterase (AChE).

for terminating the action of acetylcholine

Front 50

What are 4 Subtypes of Drugs Affecting Cholinergic Neurotransmission?

Back 50

Acetylcholine Mimetics: Muscarinic Agonists

Acetylcholinesterase (ACE) Inhibitors:
reversible
irreversible

Acetylcholine Antagonists: Muscarinic Antagonists

Nicotinic Antagonists: Neuromuscular Blocking Agents

Front 51

Acetylcholine is the prototypical muscarinic (and nicotinic) agonist, because why?

Back 51

it is the physiologic chemical neurotransmitter.

Front 52

Acetylcholine is a poor therapeutic agent why?

Back 52

because of its lack of nicotinic or muscarinic receptor specificity and because of the chemical and physicochemical properties associated with its ester and quaternary ammonium salt functional groups.

Front 53

The SAR for muscarinic agonist activity can be summarized as what?

Back 53

The molecule must possess a nitrogen atom capable of bearing a positive charge, preferably a quaternary ammonium salt.

For maximum potency, the size of the alkyl groups substituted on the nitrogen should not exceed the size of a methyl group.

The molecule should have an oxygen atom, preferably an ester-like oxygen, capable of participating in a hydrogen bond.

There should be a two-carbon unit between the oxygen atom and the nitrogen atom.