Lecture 4 Flashcards
Most drugs belonging to the same pharmacologic class have……
certain structural features in common.
for example:
-a basic Nitrogen
-an aromatic ring
-an ester or amide group
-a hydroxyl group (phenolic or alcoholic)
-an aliphatic or alicyclic portion of the molecule
similar structural features of molecules permit what?
these functional groups to be oriented in a similar pattern in space
functional groups are important in _____ interactions.
different arrangements of functional groups allow for…..
functional groups are important in BINDING SITE interactions.
different arrangements allow for HIGHLY SPECIFIC binding
what are the structural requirements for narcotic analgesic activity?
-a basic nitrogen
-an aromatic ring
-a tetrasubstituted carbon
-a 2 carbon chain linking the tetrasubstituted carbon and the basic N
name 3 narcotic analgesics.
when something has “narcotic analgesic activity” that means it affects…..
morphine
methadone
meperidine
not only are similar structures important, but also their…..
ARRANGEMENT (ie: a 2 carbon chain linking the tetrasubstituted carbon to the basic N in narcotic analgesics)
true or false
methadone and meperidine possess the same pharmacological activity as morphine
TRUE – even though they look very different
morphine, methadone, and meperidine all produce their effects by…..
binding to opioid receptors
who is the “father of med chem”
what did he say
Paul Ehrlich
he coined the term “receptors” to explain structural similarities in molecules with similar biological activity
meperidine and methadone are ___ ___
synthetic analgesics
endogenous opioid agonists
endorphins and enkephalins
true or false
the naturally produced opioid agonists (endorphins and enkephalins) produce the same effect as opioids, but through a different mechanism
FALSE – they all produce their effect by binding to opioid receptors
broadly speaking, the term “receptor” refers to…..
a relatively SMALL region of a macromolecule which may be:
-an isolatable enzyme
-a structural and functional component of a cell membrane or
-a specific intracellular substance such as a protein or a nucleic acid
receptors, most of the time, are ____ molecules
PROTEIN
Explain how receptors are visualized and how a biological response is produced when interacting with a drug
specific regions of these macromolecules (receptors) are visualized as being oriented in space in such a way that permits their functional groups to interact with COMPLEMENTARY FUNCTIONAL GROUPS OF THE DRUG
this interaction initiates a CHANGE IN THE STRUCTURE AND FUNCTION OF THE RECEPTOR (macromolecule) THAT ULTIMATELY LEADS TO AN OBSERVABLE BIOLOGICAL RESPONSE
Most drugs produce their effects by a ______ mechanism
receptor mediated
as mentioned, most drugs produce their effects through a receptor mediated mechanism.
are their any exceptions to this?
YES, there are 3 exceptions
- general anesthetics
- osmotic diuretics
- antacids
explain how osmotic diuretics do NOT produce their effects via a receptor mediated mechanism
they simply produce an osmotic gradient in the renal tubules, promoting the elimination of water in the urine
explain how antacids do not produce their effects through a receptor mediated mechanism
through an acid-base neutralization of the hydrochloric acid found in the stomach
do antacids require absorption to produce their effects?
NO
explain how general anesthetics do not produce their effects via a receptor-mediated mechanism
it is a general signal – not through a receptor
true or false
in drug design, the goal is to design drugs that are selective as possible to their receptors
TRUE – this will limit side effects
this is bc there are a variety of receptors with similar structural requirements for their ligands in multiple organs and tissues throughout the body. Receptors for the same ligand are found in multiple tissues
true or false
the role of a medicinal chemist is to design drugs that will bind selectively to the desired receptors with low affinity, so that side effects will be minimal
FALSE – HIGH AFFINITY
Give a specific example that demonstrates the need for high specificity drug-receptor interactions
there is a new class of cancer drugs called protein kinase inhibitors.
protein kinases are everywhere throughout the body, so the drug has to be VERY SPECIFIC to its target in order to receive the desired effects, and not side effects and/or toxicity
_______ of drugs influence their ability to reach the site of action AND their interaction with the receptors AFTER reaching the site of action
STRUCTURAL FEATURES
what does steric mean
the arrangement of atoms in space
what are the steric factors which influence drug activity?
(ie: ability to reach site of action, interaction with receptors after reaching the site of action)
- Isosterism
- Optical isomerism
- geometric isomerism
- conformational isomerism
isosterism, optical isomerism, geometric isomerism, and conformational isomerism all affect what?
the orientation of the drugs in space that affect drug-receptor interaction
explain the term “isostere”
refers to the groups of atoms that impart similar chemical or physical properties to a drug molecule DUE TO SIMILARITIES IN SIZE, ELECTRONEGATIVITY, OR STEREOCHEMISTRY
The ____, ____, and ____ characteristics of isosteric atoms or groups of atoms makes them…….
what is this called?
the steric, electronic, and solubility characteristics of isosteric atoms makes them INTERCHANGEABLE IN DRUGS OF THE SAME PHARMACOLOGICAL CLASS
this is the phenomenon of isosterism, or bioisosterism (when applied to med chem)
define isosterism
isostere = groups of atoms that impart similar chemical or physical properties to a drug molecule due to similar size, electronegativty, or stereochemistry
the steric, electronic, and solubility characteristics of these isosteres makes them INTERCHANGEABLE in drugs of the same pharmalogical class
this is known as isosterism
give a typical example of isosterism
“isoelectric” – same # of electrons
true or false
when replacing 1 functional group with another on the basis of isosterism (similar charge, size, electronegativity, etc) ALL PROPERTIES MUST BE SIMILAR between the new and old functional groups
false – can be just 1 similar quality, can be multiple. all depends on what quality of the original molecule that you want to maintain
give some examples of what qualities of drugs you would want to modify, on the basis of bioisosterism
-improve binding potency and/or induce side effects
-improve the duration of action
-give metabolic/chemical stability
what are the 2 classifications of bioisosteres?
differentiate them
classical and nonclassical
classical = earlier. monovalent/divalent/trivalent/tetrasubstituted and ring equivalents
nonclassical = later
exchangeable groups (ie: carbonyl and sulfonyl) and cyclic vs noncyclic structures
give examples of monovalents that are interchangeable, according to the classical bioisosteres theory.
they are interchangeable on the basis of ____ similarity
SIZE SIMILARITY
halogens (more so Cl and Br, F is too small)
-X (represents halogen)
-CH3
-NH2
-OH
-SH
thioether functional group
R-S-R
give examples of divalent atoms that are interchangeable, on the basis of classical isosterism
R-O-R’ (ether)
R-S-R’(thioether)
R-NH-R (amine)
R-CH2-R
give examples of trivalent classical bioisosteres
R-N double bond R’
R-CH double bond R’
give examples of tetrasubstituted classical bioisoteres
C with double bond R on both sides
N+ with double bond R on both sides
true or false
when swapping functional groups on the basis of bioisoterism, the addition of a full - or full + charge could be a good thing or bad thing, depending on the desired effects of the drug. the important thing is that we are able to back up the swap with scientific rationale
TRUE – can be good or bad
what is a good isostere of benzene?
thiophene, furan, pyridine
explain the rationale of why benzene can be replaced by thiophene
even though thiophene has 1 less carbon then benzene, it can still be substituted because S has a higher lipophilicity than C, so the lipophilicity of the molecule is still relatively the same even though there is 1 less carbon
benzene can be replaced with pyridine. explain why this can potentially pose an issue
the electronegativity is slightly different, being that in pyridine, the electrons are unevenly distributed (more polar) than in benzene
under classical isosteres, methyl can be replaced with chlorine.
what is an important consideration with this?
SIZE is being maintained, but NOT electronegativity
with the intent of maintaining both size AND electronegativity, what can Cl be replaced with?
if only size were a concern, what could it be replaced with?
to maintain both size and electronegativity, replace Cl with CF3
to maintain just size, replace with methyl
carbonyl and sulfonyl are nonclassical bioisosteres
what is an important consideration when replacing one with the other?
the 2 are NOT isoelectric, but may have a similar polarity
true or false
carboxylic acid and sulfonic acid have similar electronegativity
true
a nonclassical bioisostere of amides is _______
why is this useful?
sulfonamides
amides are easily hydrolyzed in the GI tract. Replacing amide with sulfonamide can prevent premature hydrolysis in the GI tract.
this is used in peptide drugs which have an issue with metabolic instability. peptide drugs are made of amino acids and there are many proteases in the GI tract. the drug may not survive.
thus, the least destructible way of resolving this is by replacing with a sulfonamide which is NOT HYDROLYZED BY PROTEASES.
but, it must be considered – will this negatively affect drug activity?
the nonclassical bioisostere of carboxylic acid is sulfonic acid.
what is an important consideration?
sulfonic acid is much more acidic.
the 2 may have similar electronegativities, but acidity difference may pose an issue
NONCLASSICAL bioisosteres are replacements of….
functional groups
