Lecture 3 cont Flashcards
Neutral fats make up ____-____% of body weight
20-50%
the more lipophilic the drug, the ____ likely it will deposit in neutral fats
MORE
what are the mechanisms in which lipophilic drugs deposit in neutral fats?
either:
- Direct physical dissolution
- primary deposition into membranes, follows by slow redistribution into fatty tissue
give an example of drugs that get deposited into neutral fats.
what is the effect of this?
ultra short acting barbiturates (such as thiopental)
thus, these drugs have a VERY SHORT DURATION OF ACTION because they are deposited into these neutral fats, thus decreasing its plasma concentration below therapeutic levels.
this could be intentional
does sulfur increase or decrease lipophilicity
in organic molecules, sulfur INCREASES lipophilicity (except when bound to hydrogen)
what is thiopental
a sulfur containing, ultra short acting barbiturate that gets deposited into neutral fats, thus having a very short duration of action
what does QSAR stand for
quantitative structure-activity relationship
QSAR studies were originally performed by whom and when
Hansch in the 1960s
true or false
QSAR studies began in the 1960s and are still evolving
true
Hansch performed studies to correlate what?
he wanted to correlate the CHEMICAL STRUCTURE and PHYSICAL PROPERTIES of the drug to its biological activity
what is THF
Tetrahydrofuran – an organic solvent
What does LD50 mean
the dose at which 50% of the test sample is killed. Lethal dose
what is ED50
effective dose – the dose at which 50% of the population gets treated effectively
give the formula for the rate of the drug response, according to QSAR
Rate of response = d[Response]/dt = ACkx
A = probability of molecule reaching the site of action
C = extracellular drug concentration
Kx = rate (or equilibrium) constant
in QSAR, what are the 3 parameters used to correlate the chemical structure, physical properties, and biological activities of a drug?
-lipophilic parameter (pi)
-electronic parameter (sigma)
-steric parameter (Es)
what does the lipophilic parameter (pi) of QSAR indicate?
the relative lipid solubility
a positive p value in QSAR indicates what?
a positive p value means that the substituent will cause an increase in lipid solubility
give the equation of QSAR
Log 1/C (A) = -k(pi) squared + k’pi + p sigma + k”
A= probability of the molecule reaching the site of action
C = extracellular drug concentration
pi = lipophilic parameter
sigma = electronic parameter
in the QSAR formula:
log1/C (A) = -kpi^2 + k’pi + psigma + k”
which are variables?
which are constants?
constants = k, k’, k”, p
variables = pi, sigma
Hansch proposed his equations to measure the ___, ____, and ___ contributions when a molecule is…..
this is helpful for what?
Hansch proposed his equations to measure the LIPOPHILIC, ELECTRONIC, AND STERIC contributions when a molecule is SUBSTITUTED BY VARIOUS GROUPS.
this is helpful in drug design
Alkyl (–R) and Alkoxy (R–O) are typically electron withdrawing or donating?
donating
what is a nitrile group
are they electron donating or withdrawing?
R-C triple bond N
the most electron withdrawing group
are halogens electron donating or withdrawing?
name the halogens
withdrawing
fluorine
chlorine
bromine
iodine
astatine
teenessine
what is an alkoxy group?
are they electron donating or withdrawing?
donating
alkyl with a single bond to oxygen
amine groups are electron donating or withdrawing?
donating, as long as it doesnt become protonated in aliphatic/aprotic conditions
the lipophilic parameter gives what?
the relative lipid solubility
what is the rate limiting condition for a drug to reach the site of action?
movement through a series of membranes
since the rate limiting conditions for reaching the site of action involves movement through a series of membranes, _______ has become the most important physiochemical measurement for QSAR studies
PARTITION COEFFICIENT
what value is the “relative lipid solubility profile”
partition coefficient
p substituent=…….
a positive p value means what?
p substituent = log PC (substituent molecule) - log PC (parent molecule)
a positive p value means the substituent will cause in INCREASE IN LIPID SOLUBILITY
True or false
when added as substituents, halogens cause a decrease in lipophilicity
FALSE
they actually contribute to lipophilicity a pretty substantial amount
is carboxamide a polar or nonpolar substituent?
will in cause an increase or decrease in PC?
polar substituent. will cause a decrease in PC
will COCH3 group cause increase or decrease in PC
decrease
COCH3 = acetyl
will nitrile group cause increase or decrease in PC
decrease
CN
hydrophiliv
will alkyl groups cause an increase or decrease in PC
increase
true or false
the more carbons in an alkyl group, the more it will contribute to an increase in PC
true
the lower the pi, the _____ hydrophilic
more
the higher the sigma value, the more electron _____ it is
withdrawing
the higher the ES, the ____ it is
larger
when looking at QSAR and multiple formulas are generated with relatively the same correlation coefficients (r squared), which equation should you pick?
the shortest variable containing equation
to obtain maximal activity……
maximize log A. use small, potent dose
