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PHAL211 > Module 1 > Flashcards

Module 1 Flashcards

1
Q

what is an endocannabinoid?

A

an endogenous cannabinoid (your body makes it naturally)

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2
Q

whar are endocannabinoids responsible for?

A

regulating immune response, communication between celll, appetite and metabolism, memory and more.

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3
Q

what is CB1

A

a G-protein coupled receptor that sits in the cell membrane and when it is activated by THC or something similar it activates G-proteins that lead to a series of intracellular events.

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4
Q

what is a ligand

A

a substance that forms a complex with a biomolecule to serve a biological purpose

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5
Q

what is the difference between an endogenous and exogenous substance?

A

Endogenous substances and processes are those that originate from within a system such as an organism, tissue, or cell. Endogenous substances and processes contrast with exogenous ones, such as drugs, which originate from outside of the organism

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6
Q

what is a synthetic cannabinoid and what does it do in the body?

A

Synthetic drugs contain a mixture of psychoactive compounds that mostly bind cannabinoid receptors with high potency. These synthetic drugs replicate the effects of natural cannabis and Δ9-tetrahydrocannabinol but they induce more severe adverse effects including respiratory difficulties, hypertension, tachycardia, chest pain, muscle twitches, acute renal failure, anxiety, agitation, psychosis, suicidal ideation, and cognitive impairment

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7
Q

what kind of axis does sigmoidal concentration-response curves have?

A

log molar axis

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8
Q

the ability to drive a response/the size of the response being produced is defined by the…

A

efficacy

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9
Q

the concentration at which the response occurs is defined by the…

A

potency

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10
Q

how strongly the drug binds to the receptor is defined by the…

A

affinity

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11
Q

what is a partial agonist?

A

a drug that binds to a receptor but is not good at activating it and doesn’t produce a maximal response

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12
Q

does AMB FUBINACA or THC have a higher affinity?

A

AMB FUBINACA has a 50 fold higher affinity than THC because it takes less drugf to occupy 50% of the receptors

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13
Q

does AMB FUBINACA or THC have a higher potency?

A

AMB FUBINICA has a 14 fold (14 times more potent) higher potency than THC

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14
Q

does THC recruit beta-arresting 2 to the cell surface?

A

no, but AMB FUBINACA does

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15
Q

what experiments can be done to find the difference between AMB FUBINACA and THC

A

measure affinity, the inhibiton of cAMP, the phosphorylation of ERK and beta-arrestin 2 recruitment and internalisation

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16
Q

What Is the difference between a drug and a medicine?

A

A drug is a chemical substance of a known structure other than a nutrient or an essential dietary ingredient which when administered to a living organism produces a biological effect and a medicine is a chemical preparation which usually contains one or more drugs, administered with the intention or producing a therapeutic effect. Medicines usually contain other substances to make them more convenient to use. And medicines face strict legal requirements.

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17
Q

What are drug actions dependent on?

A

they are dependent on chemical properties and dependent on biological molecular targets

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18
Q

what does being dependent on chemical properties mean in terms of drug actions?

A

they do not interact with cell components and instead produce an effect via a chemical reaction

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19
Q

what are the 4 primary protein drug targets?

A

receptors, ion channels, carrier molecules/tranporters and enzymes

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20
Q

what are the 2 steps of drug receptor interactions?

A

occupancy (governed by binding affinity) and activation (governed by efficacy)

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21
Q

what do receptors do in terms of being a drug target?

A

they are recognition molecules which allow for detection of chemical message. they are often but not always on cell surface

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22
Q

mimicking endogenous ligand

A

agonist

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23
Q

blocking endogenous messengers

A

antagonist

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24
Q

what chemical interactions do drugs use to bind to receptors?

A

vanderwall (weak forces)
hydrogen binding (stronger)
ionic interactions (stronger than hydrogen but weaker than covalent)
covalent (essentially irreversible)

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25
Q

what is the law of mass action

A

the rate of a chemical reaction is proportional to the product of the concentrations of reactant. the total amount of receptor is constant throughout so at any time the amount of unbound receptor R is going to be equal to the total receptor number less the amount bound to the drug

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26
Q

Receptor/receptor agonist complex

A

equlibrium constant

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27
Q

what are the units for Ka

A

L/mol

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28
Q

Kd = K-1 / K+1

A

dissociation constant

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29
Q

what are the units for Kd

A

mol/L

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30
Q

[RA] / [Rtot]

A

fraction of receptor bound

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31
Q

K+1 [A] [R]

A

rate of forward reaction

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32
Q

K-1 [RA]

A

rate of reverse reaction

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33
Q

define affinity

A

a measure of the drugs ability to bind to the receptor, it is defined by the Kc which is the concentration of the drug required to occupy 50% of the receptors

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34
Q

Define potency

A

a measure of the concentration of the drug required to reach 50% of the maximal response. EC50 is used to measure a drugs potency, it is not the same as affinity because not all the receptors have to be occupied to get the same response

35
Q

Define efficacy

A

the ability of a drug to bind to a receptor and cause a change in the receptors actions, measured by Emax

36
Q

Define a agonist and partial agonist in terms of drug efficacy

A

A drug with a positive efficacy will activate a receptor to promote cellular response (agonist). Drugs that produces less than maximal response -even at 100% receptor occupancy is a partial agonist. so therapeutically we want a partial agonist to drive the receptors more gently

37
Q

define reversible competitive antagonism

A

a drug that binds non-covalently to a receptor, its competitive so it binds to the same site as the endogenous agonist (orthosteric) and an antagonist is a drug that has affinity but no efficacy and the effects from this drug will be surmountable so the action of the agonist can be restored by increasing the concentration of the agonist.

38
Q

what is an example of a reversible competitive antagonist

A

Naloxone which is an opoid antagonist and used to treat overdose with heroin or prescription optic pain medications (agonist)

39
Q

define irreversible competitive antagonism

A

a covalently bound drug to the receptor orthosteric site, its effects are not surmountable so it cannot be overcome by increasing the concentrations of the agonist. It reduced the number of available receptors for the agonist because it binds irreversibly, the receprots are taken out and eventually you wipe them all out.

40
Q

what is an example of a irreversible competitive antagonist

A

phenoxybenzamine that binds to alpha-adrenergic receptors

41
Q

when does a irreversible antagonist look like a reversible antagonist on a response curve?

A

at low doses an irreversible antagonist looks like a reversible antagonist because there are more receptors available than you need so it will have the same response curve up until it reaches a certain concentration when the response decrease

42
Q

what is a full agonist

A

they are agonists that produce a response even though not all the receptors are occupied, some receptors remain unbound by a ligand and these are sometimes called spare receptors and the presence of the spare receptors increases the potency of an agonist.

43
Q

why do we have spare receptors?

A

for example at the NMJ there are thousands of spare ACh receptors incase of an injury. Muscles achieve maximum contraction by only activating a small fraction of the receptors

44
Q

what is competitive reversible inverse agonism

A

an inverse agonist prevents constitutive activity (not all receptors require an agonist bound for activity), they have affinity but a negative efficacy`

45
Q

what shifts the equilibrium strongly towards the R* (on state)

A

agonist

46
Q

what shifts the equilibrium partially towards R* (on state)

A

partial agonist

47
Q

what shifts the equilibrium strongly towards R (off state)

A

inverse agonist

48
Q

what doesn’t shift the equilibrium

A

antagonists

49
Q

why do we use an inverse agonist

A

for diseases caused by overactivity of the receptor and antagonists do not alter constitutive activity so would be ineffective

50
Q

what would an inverse agonist do in an agonist response curve?

A

an inverse agonist removes the basal activity so it will reach maximum and there will be a rightward shift on the response curve

51
Q

what is the orthosteric binding site

A

the endogenous agonist binding site

52
Q

what is an allosteric modulator

A

ligands that bind to an allosteric site to modulate the binding and or signaling properties of the orthosteric binding site

53
Q

what might an allosteric ligand do?

A

increase/decrease affinity of the orthosteric ligand
increase/decrease efficacy of the orthosteric ligand
activate the receptor directly (allosteric agonist)

54
Q

what is the ceiling effect

A

when there is no further response possible

55
Q

compare and contrast inverse agonism and competetitive reversible antagonism

A

both are said to have affinity because they bind tightly to the receptor, and in regards to efficacy, the inverse agonist has negative efficacy because its produces the opposite response to the endogenous agonist and the competitive reversible antagonist has no efficacy because it drives no response.
They are both binding orthosterically, they are both binding competitively to the orthosteric binding site, but the difference is that the inverse agonist decreases basal activity where as the antagonist has no effect on binding. They both prevent agonists from binding

56
Q

what are the 2 different types of ion channels?

A

Ligand-gated and voltage gated

57
Q

What is parkinsons disease and what drug can be given?

A

a loss of dopamine in the brain, it doesn’t cross the blood-brain barrier so cannot give straight dopa one as a cure. L DOPA can cross the barrier then enzymatically be made into dopamine in the brain

58
Q

what are the two types of enzyme inhibition and what are they?

A

non-competitive inhibition - allosterically bind to a different site and cause a conformational change to activity
competitive inhibition - prevents substrate from binding, it is a competitive interaction and the most common type of enzyme inhibition.

59
Q

what is a zenobiotic?

A

a chemical substance found within an organism that is not naturally produced or expected to be present within
the organism. It can also cover substances that are present in
much higher concentrations than are usual.

60
Q

what does a P-glycoprotein recognize

A

foreign things to the body and tries to get rid of them, it pumps things out of cells

61
Q

what is a drug that inhibits P-gp?

A

verapamil - increases the bioavailability of susceptible drugs

62
Q

what drug induces P-gp?

A

rifampicin reduces the bioavailability of some drugs

63
Q

what is the serotonin (5HT) transporter involved in

A

appetite, sleep, memory, sexual behavior, neuroendocrine function and mood

64
Q

how many transmembrane domains does a serotonin transporter have?

A

12

65
Q

is an inhibiting or enhancing drug easier to design?

A

an inhibiting drug because drugs that inhibit bind to the active site whereas drugs that enhance have to bind elsewhere and increase its ability to transport something across the cell membrane (increase efficacy and potency which is a complex drug action). If you want to make an enzyme better you have to make an allosteric substrate.

66
Q

Ligand-gated ion channels

A
  • control muscle transmittion
  • mediate fast signal response
  • 4 or 5 subunits
  • activated in response to specific ligands
67
Q

ligand gated ion channels as drug targets: GABA a

A

Benzodiazepines

68
Q

Ligand gated ion channels as drug targets: glutamate

A

ketamine

69
Q

Ligand gated ion channels as drug targets: nicotinic

A

nicotine

70
Q

The kinase linked receptor family

A
  • mediated the actions of growth factors, cytokines and certain hormones
  • their effects are mainly on gene transcription
  • long chain of amino acids
  • there are 3 different types of them
  • single transmembrane domains
71
Q

whar are the three different types of kinase linked receptors?

A
  • receptor tyrosine kinase
  • receptor serine/threonine kinase
  • cytokine receptors
72
Q

how the serotinin transporter works:

A

-Na+ binds first to the carrier followed by 5-HT (1). Cl- is
needed for transport but not for transmitter binding
- the molecules are translocated in the membrane and dissociate (2). K+ then binds (3) and it translocated to
the outside of the membrane (4), and dissociates to
complete the cycle.

73
Q

name a drug that works at a ligand gated ion channel and how

A

An example of a ligand-gated ion channel is the nicotinic acetylcholine receptor that is at the skeletal neuromuscular junction, the autonomic ganglion of the sympathetic nervous system and in the brain, it is a pentameric structure made of a combination of 4 subunits. The subunits cluster around the central receptor channel and each of the subunits has 4 transmembrane domains (20 TM domains in total). Each receptor has 2 ACh binding sites and both sites have to be activated to open, the binding site is formed by peptide loops on an alpha subunit and on an adjacent subunit. When ACh binds it causes a conformational change and it straightens out the kink in one of the subunits and it opens and allows ions to pass through. The second transmembrane helices of each subunit kink inwards forming a constriction and they snap into attention when Ach binds.

74
Q

describe a nuclear receptor

A

slow-acting response
ligand needs to cross over into the cell (must be lipid soluble)
might be in cytoplasm or nucleus
induce changes in gene transcription and protein synthesis

75
Q

What is the structure of a nuclear receptor?

A

monomeric protein with an N-terminal activation binding site, DNA binding domains that bind to hormone resins elements in DNA. A flexible hinge region that allows the proteins to form large globular structures, a ligand binding domain and a C-terminal activation where co activation or co repressors bind and express their effects

76
Q

describe the 2 major classes of NRs

A

Nuclear receptors sense lipid and hormone signals to modulate gene transcription. Class one in complexes in the cytoplasm, form homodimers upon binding ligand, migrate to the nucleus; they are mainly endocrine ligands. Class 2 are present in the nucleus, form hetrodimers with RXR; mainly lipid ligands.

77
Q

describe the structure of a GPCR

A

A G-protein coupled receptor is a single protein that different in the ligand binding domain, they all have 7 transmembrane domains with an extracellular N terminal and a intracellular C terminal. the conformational change of them leads to the activation of a G protein.

78
Q

Describe the G protein activation cycle

A

When the agonist/ligand binds it causes GDP to be replaced with GTP and this causes G alpha to dissociate from gamma and beta. the Alpha subunit with GTP attached goes to and activates the target proteins causing GTP to be hydrolyzed back to GDP and it goes back to the resting state

79
Q

what does Gq activate

A

the phospholipase C (PLC) pathway

80
Q

what does Gs activate

A

it activates cAMP and protein kinase C (PKC) pathway

81
Q

what can activated protein kinase do within the cell?

A

increased lipolysis, reduced glycogen synthesis and increased glycogen breakdown

82
Q

what is the role of presynaptic receptors in neurotransmitter release?

A

inhibit or facilitate the release of a given transmitter from its axon terminals

83
Q

what is a common way to turn off a receptor?

A

clathrin-coated pit formation, being invagilated and inactivated

84
Q

what is the receptor regulation of a GPCR?

A

Receptor recruits a G-protein receptor kinase that will phosphorylate its C-terminal, once it it is there, the receptor can no longer interact with the G-protein so now it is desensitized, essentially turned off
The phosphorylated receptor recruits another protein which is called an irestin which binds to the phosphorylated C-terminal and then the irestin receptor complex can recruit a series of molecules involved in clathrinp-coated pit formation, this leads to the part of the cell membrane the receptor is sitting in being invagulated (form pit), and then being internalized.

PHAL211 (2 decks)

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