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Med Chem 625 > Unit 1 (Quiz 1) > Flashcards

Unit 1 (Quiz 1) Flashcards

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1
Q

What does chemical structure determine, and what does it therefore influence?

A

chemical structure determines physiochemical properties and influences biological activity

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2
Q

What is SAR?

A

Structure-Activity Relationships: the study of how changes to the structure of a compound affect the biological activity

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3
Q

What kind of effects can small changes have on the magnitude and direction of a biological activity?

A

profound effects

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4
Q

What kind of biological activities do similar molecules have in relation to each other?

A

similar biological activities

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5
Q

What are the three drug examples that when methylated, produce different biological activities, and what are these new activities compared to the original activities?

A
  1. morphine (analgesic)- N-methylmorphine (muscle relaxant)
  2. nicotine (CNS stimulant)- N-methylnicotine (muscle relaxant)
  3. atropine (mydriatic or dilates pupil)- N-methylatropine (muscle relaxant)
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6
Q

For the drug tubocurarine, a plant extract used as dart poison, where does its main activity occur, and why is its biological activity similar to those of methylated morphine, nicotine, and atropine?

A

quaternary amine; b/c the three drugs have the same site/functional group activity

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7
Q

What are some common reasons for developing a new drug? (11)

A

no current treatment for disease; a drug is too easily metabolized; lack of site selectivity; absorbed too quickly; water insoluble (not absorbed); formulation probs; poor absorption (GI, BBB); chemically unstable drug; intolerance or irritation; poor dr./nurse acceptance; poor patient acceptance

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8
Q

Where do new drugs come from? (9)

A

natural products (earliest); random screening (test millions); combo chemistry (mix n’ match peptides); privileged motifs (core structs grouped); literature and patents (structural clues to make new similar drugs); ligand design (computational-based); endogenous ligands (good starting pts); chemogenomics (family of related molecules tested in parallel)

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9
Q

What are some factors that should be take into consideration that make drug development very complex? (8)

A

ADME, potency, efficacy, selectivity, protein-binding

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10
Q

What must occur when a drug reaches a target in order to produce the desired biological effect?

A

the two must recognize each other and bind (drug-target complex) to begin process

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11
Q

What factors of drug target sites are critical for binding? (3)

A

most targets are proteins, and they are chiral and 3-D

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12
Q

What are some properties of drug molecules? Are there exceptions? (4)

A

low MW, not too lipophilic, not too hydrophilic, presence of functional groups- these interact with complimentary sites; Yes

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13
Q

What are some properties of drug targets? (3)

A

usually a protein, leads to biological response, does not cause toxicity at therapeutic dose

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14
Q

What types of stereochemical property do the ligand interactions of chiral drug targets have?

A

they are stereoselective

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15
Q

Do two enantiomers have the same biological activity?

A

No, activity resides mostly in one over the other

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16
Q

What is Pfeiffer’s Rule concerning enantiomers and biological activity?

A

the preference for one enantiomer over the other often increases with and increase in receptor infinity; increase potency= increased selectivity

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17
Q

What is on-target toxicity? What is a clue that may indicate this?

A

a side effect that may occur as soon as a therapeutic dose of drug reaches the target site; if the ratio of doses that cause the desired effect and the side effect is the same for the two enantiomers (ED50 drug/ED50 ent drug) = (TD50drug/TD50 ent drug)

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18
Q

What is the Easson-Stedman Hyporthesis concerning optical isomers?

A

Receptors are chiral macromolecules, so optimal chirality is required for optimal drug action

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19
Q

What is the “lock and key” hypothesis in relation to the Easson-Stedman hyopthesis and optical isomers?

A

both thedrug and the receptor are rigid

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20
Q

What is the minimum necessary feature of optical isomers to distinguish between enantiomers?

A

there must be three points of attachment, and these points of attachment must be in line with the binding sites; for example, R-(-)EPI has 3 points of attachment, but S-(+)EPI, though having the same chiral groups, does not have its -OH group in line with site B

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21
Q

What is the main difference between enantiomers and diastereomers?

A

enantiomers are non-superimposable mirror images, while diastereomers are non-superimposable non-mirror images of each other; also, if a molecule has more than one chiral group, diastereomers will only be rotated around one chiral center

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22
Q

(-)-Ephedrine and (+)-Ephedrine are almost identical. In which environment are they distinguishable?

A

stereochemically in a chiral environment, which is the human body

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23
Q

What are the four main chiral effects on drug behavior?

A

ADME

24
Q

Why might a less active enantiomer possess toxicity or SEs not prominently associated with more active ones?

A

B/c the less active enantiomer fits the receptor more loosely, and it may be interacting with something else since its bond to the receptor is not as strong as the more active enantiomer; in other words, less active enantiomers may have off-target effects

25
Q

Occassionally, two enantiomers may possess different biological activities. What drug is an example of this, and what are the two different activities?

A

Sotalol; one is beta-adrenergic and one inhibits K+ channels

26
Q

VERY occasionally, metabolic inversion can occur. What does this mean, and what two drugs does this happen to, and what are the repercussions?

A

Basically the drugs are sold in racemic mixtures; that is, they are a 50:50 ratio of the drug’s two types of enantiomers. IBU- one ent has anti-inflammatory and pain-killing effects, and the other gets converted to the one ent; thalidomide- one has angiogenic properties while the other helps with morning sickness from pregnancy

26
Q

VERY occasionally, metabolic inversion can occur. What does this mean, and what two drugs does this happen to, and what are the repercussions?

A

Basically the drugs are sold in racemic mixtures; that is, they are a 50:50 ratio of the drug’s two types of enantiomers. IBU- one ent has anti-inflammatory and pain-killing effects, and the other gets converted to the one ent; thalidomide- one has angiogenic properties while the other helps with morning sickness from pregnancy

26
Q

VERY occasionally, metabolic inversion can occur. What does this mean, and what two drugs does this happen to, and what are the repercussions?

A

Basically the drugs are sold in racemic mixtures; that is, they are a 50:50 ratio of the drug’s two types of enantiomers. IBU- one ent has anti-inflammatory and pain-killing effects, and the other gets converted to the one ent; thalidomide- one has angiogenic properties while the other helps with morning sickness from pregnancy

27
Q

Most drugs bind non-covalently/ reversibly to their targets. Why is this?

A

B/c permanently inactivating targets through covalent/irreversible binding leads to toxicity or allergy due to the immune system going after these covalently-bonded proteins

28
Q

What are the benefits to non-covalent bonds between drugs and their targets? How does this relate to equilibrium?

A

they have sufficient strength and durability to modulate the activity of a target for a finite period of time and then release the association. This creates an equilibrium state that is subject to kinetic analysis

29
Q

What is the most important requirement between a ligand (drug) and its target?

A

good steric and electronic (charge) complementarity; ex: enough room (no steric hindrance), opposites attract

30
Q

What types of bonds are electrostatic bonds? What molecule plays a significant role?

A

strong(est) and orienting- help with docking of drug to receptor; when the approach is close, secondary bonds (H+, Van der Waals) come into play; water plays a significant role through H-bonding with both partners which compensates for necessary water loss from both partners when they interact

31
Q

In hydrophobic bonding, what type of approach is needed for the molecules to bond? How can these molecules be separated?

A

to bond, the molecules need a closeness approach. to separate, they must be rehydrated

32
Q

in aryl-aryl interactions, what are the three conformations that can take place because of the rings containing polarized substituents?

A

pi-stacking, edge-to-face, and parallel-displaced stacking

33
Q

when considering hydrogen bonds, what matters the most concerning conformation? which two are most favored? what is the strongest hybridization?

A

geometry matters! six-membered rings are favored, and five-membered rings are next in strength. sp2

34
Q

what is the difference between intramolecular hydrogen bonds and hydrogen bonds? how does this difference affect water solubility, lipophilicity, and uptake? which conformation is highly favorable? what can make intermolecular interactions with H+ easier?

A

intramolecular hide donor and acceptor groups from the bulk solvent (create a “ring”). decrease water solubility, increase lipophilicity, and increase uptake. 6-membered ring. stripping H20 molecules from main molecule

35
Q

rank non-covalent ligand/drug receptor bond types from most to least strong

A

electronic (ionic), hydrogen (charge assisted are stronger), non-polar (hydrophobic), and van der waals

36
Q

what is the minimum structural unit of a molecule that will interact with a receptor leading to a characteristic pharmacological response? what happens if you delete this?

A

pharmacophore; completely loses activity, becomes inactive

37
Q

what is the non-essential portion of a drug molecule that supports the pharmacophore and so modulates the pharmacokinetics and selectivity of a drug? what happens if you delete/replace this?

A

auxophore; has minimal effects because not main bio activity

38
Q

what are chemical substituents with similar physical/chemical properties that produce similar bio effects in the context of a larger molecule (swapping one functional group with another that is similar in size)? what is the purpose of exchanging these?

A

bioisosteres; enhance drug activity without drastically changing the chemical structure, reduce toxicity, change bioavailability, modify activity of lead compound, alter metabolism

39
Q

what are nonclassical bioisosteres?

A

molecules that are biologically equivalent in interactions with receptors

40
Q

what is the “Rule of 5” in drug development? what does this rule NOT predict?

A

<5 H bond donors
<10 H bond acceptors
MM <500 daltons
oct-water partition coeff (LogP) <5
# of rotatable bonds <5

does NOT predict if drug is pharmacologically active

41
Q

What are some (8) molecular design principles that may be used to improve drug-like properties of a molecule with some type of deficiency?

A

bioisosteric replacement
conformational constraint (chain becomes ring= no cost in receptor binding)
homologation (shorten/lengthen chain to be optimal for binding)
alteration of stereochemistry (invert)
molecular dissection (unnecessary part)
alteration of interatomic distances
intro of fluorine (valuable to prevent metabolism)
modification of H bonding

42
Q

what is a fundamental assumption about drug action regarding pharmacological response of a drug and its concentration?

A

the pharm response of a drug is directly related to its concentration at the site of action

43
Q

what is a fundamental assumption about drug toxicity in regards to concentration?

A

all drugs are toxic if the concentration at the site of toxicity can be reached

44
Q

What is the safety margin as defined by a ratio? What is another name for this? What do these terms (in the ratio) mean? do we want this number (ratio) to be high or low?

A

it is the ration between ED50- therapeutic effect in 50% of subjects and TD50- dose that results in toxic effect in 50% of subjects; we want this to be as high as possible!

45
Q

what is the fraction of administered drug that reaches the systemic circulation?

A

bioavailability

46
Q

we need a good balance between water and lipid solubility to have high drug action. what happens if you have too high of water solubility and low action? what happens if you have too high of lipid solubility and low action?

A

drug has difficulty passing bio membranes; drug doesn’t dissolve, and can’t pass gut lining which means it won’t be absorbed

47
Q

what characteristic must drugs have in order to pass through membranes? what molecule is used to represent this in the partition coefficient?

A

lipophilicity; 1-octanol

48
Q

what is used to measure the balance between hydrophilicity and hydrophobicity?what does it mean if you increase this number?

A

partition coefficient; increase P=more lipophilic

49
Q

what does log P estimate in regards to molecules? what is the ratio if you have a log P value of -2? log P of 5?

A

bioavailability; 1 oct: 100 water; 10^5 oct: 1 water

50
Q

what are the different mechanisms of membrane transport (5)? describe

A

transcellular passive diffusion- requires lack of ionization and balance of water and lipid solubility
paracellular diffusion- fit between cells, pass through pores
facilitated diffusion- high to low concentration with protein helper
transcytosis- fuse to membrane
active efflux- expel drug out of cell, active, needs E, low to high concentration via ATP hydrolysis

51
Q

in the fluid mosaic model of bio membranes, what is the most common route for drugs to be transported through membranes?

A

passive uptake

52
Q

in the fluid mosaic model of bio membranes, what must take place in order for passive uptake to work properly?

A

desolvation-solvation

53
Q

From where does active transport get energy to for movement through channels, and in what direction (gradient)?

A

ATP hydrolysis; low to high (against)

54
Q

what is the role of P-gp in membrane transport, and what type of transport is it used in? what model is it used in?

A

interacts with drug in lipid bilayer and is subsequently secreted back into EC space (spits drug molecule out using energy via active transport); active transport; vacuum cleaner model

55
Q

what are the three main transporter types and describe? (also two subcategories of last one)

A

facilitated- down gradient (H->L), no E needed
primary active- uses ATP for E; against gradient (L->H)
secondary active- uses E from [C] gradient of co-transported molecules
- antiport: H->L; uses E from co-transport
- symport: one with and one against gradient; with gradient has H going in cell; against gradient has drug going in cell

Med Chem 625 (1 decks)

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