IMC 03 and 04: Physicochemical Properties of Drugs I

Question 1

What is quantitative structure-activity relationships (QSAR)?

Answer 1

quantitative relationships between the physicochemical properties of compounds with their pharmacological activity

• pharmacological actions of a drug are a function of physicochemical parameters (ie. solubility, lipophilicity, electronic effects, ionization, stereochemistry, sterics, etc.)

Question 2

HA Acid (Bronsted Acid)

Answer 2

positively charged when protonated

Question 3

BH+ Acids (Bronsted Base)

Answer 3

• positively charged when protonated
• neutral base when dissociated

Question 4

What is Ka?

Answer 4

proton dissociation equilibrium constant that bears the unit of molarity

• products (H+ and A-) divided by reactants (HA)

Question 5

pH < pKa

Question 6

pH = pKa

Question 7

pH > pKa

Answer 7

• HA acid: A- predominates
• BH acid:

Question 8

HA Acid

pKa within 2 pH units…

Answer 8

• start to see ionization
• after 2 pH units in the positive direction, 99% ionized

Question 9

BH Acid

Answer 9

• 99% ionized when pH < pKa
• when pKa is within two pH units,

Question 10

Henderson-Hasselbalch Equation

If pH - pKa > 0. . .

Answer 10

numerator is the predominant species

Question 11

Henderson-Hasselbalch Equation

If pH - pKa < 0. . .

Answer 11

denominator is the predominant species

Question 12

What is the hammett substituent constant (σx)?

Answer 12

measure of the electron-withdrawing or electron-donating ability of a substituent

• this value is determined by measuring and comparing dissociation equilibria for a series of substituted benzoic acids to the dissociation of benzoic acid itself (ie. loss of the proton)

Question 13

Electron Donating Group (EDG)

Answer 13

• KaX < Ka
• molecule will have higher pKa

Question 14

Electron Withdrawing Group (EWG)

Answer 14

• KaX > Ka
• molecule will have lower pKa

Question 15

σx Equation

Answer 15

used to quantify the electronics of a group to its contribution to the pKa value of benzoic acid

• negative for EDGs
• positive for EWGs

Question 16

What is Hammett’s postulate?

Answer 16

electronic effects (both inductive and resonance) of a set of substituents should be similar for different organic reactions

Question 17

What are inorganic salts?

Answer 17

created by the reaction of:

• acidic drug with inorganic base (ie. NaOH or KOH)
• basic drug with inorganic acid (ie. HCl, or H2SO4)

Question 18

What are organic salts?

Answer 18

created by the reaction of an acidic drug with an organic base (ie. dimethylamine or lysine) or a basic drug with an organic acid (ie. succinate or citrate)

Question 19

What is topological polar surface area (TPSA)?

Answer 19

surface area sum (A2) of a compound over all polar atoms

• ie. specifically heteroatoms nitrogen, oxygen, and sulfur
• correlates with water solubility

Question 20

What is the partition coefficient (P)?

Answer 20

the commonly used parameter to describe hydrophobicity/hydrophilicity

• measure of a compound’s ability to partition between 1-octanol and water
• tries to provide a workable parameter for the diffusion of drugs across a biological membrane
• difference between concentrations of a compound in octanol and water can be quite large, therefore P is converted into a log10 exponent – this hydrophobicity metric is routinely referred to as logP

Question 21

What is the hydrophobicity substituent coefficient (πx)?

Answer 21

theoretical logP values can be calculated based on a lead compound plus contributions from different substituents that have been determined in other QSAR experiments

• for a given substituent (X) on a molecule, a hydrophobicity constant (πx) can be added to the logP value of a parent/non-substituted compound (logPH)
• molecule’s hydrophobicity is the sum of its parts
• logPx = logPH + x1 + x2+ . . .

Question 22

What is required for a drug to cross the blood-brain barrier (BBB)?

Answer 22

logP ≥ 2

• BBB is a protective network of capillaries and cells that prevent passive diffusion of hydrophilic molecules into the central nervous system (CNS)
• ionizable compounds that have pKa values between 6-8 readily pass the BBB – prediction made on ionized structure (not neutral)

Question 23

What is the distribution coefficient (D)?

Answer 23

partition coefficient (P) at a specific pH

• measure of an ionizable compound’s ability to partition between 1-octanol and water at a particular pH (typically pH 7.4)
• takes into account the fact that ionization of compounds leads to a greater water solubility than what can be predicted from the neutral structure
• like partition coefficient (P), it is expressed as the exponent logD(pH)

Question 24

What is molecular weight (MW)?

Answer 24

mass of one molecule of a substance, measured in atomic mass units (amu)

• often expressed confusingly as grams per mole (molar mass units) or Daltons (Da)

Question 25

What are rotatable bonds?

Answer 25

any single bond not in a ring bound to an internal non-hydrogen atom