Phar chem 11/10/14 lecture

New Postulates

• Ligand, use of

• Recombinant DNA

• Genome mapping

New Postulates

THE RECEPTOR

• Humans (and mammals in general) are very complex organisms that have developed specialized organ systems.

• It is not surprising that receptors are not distributed equally throughout the body.

• Ex. Tamoxifen is used for estrogen-sensitive

breast cancer and for reducing bone loss from osteoporosis

SUMMARY

• Altering the molecule to change the bio-distribution.

• Searching for structures that show increased specificity for the target receptor that will produce the desired pharmacological response while decreasing the affinity for undesired receptors that produce adverse response.

• Attaching the drug to a monoclonal antibody that will bind to a specific tissue antigenic for the antibody.

PhosphodiesteraseType 5 inhibitors.

Acid+ Base

• an acid is a proton donor and a base is a proton acceptor.

Common Acid Base Conjugation

Acid Base Conjugation

How to predict which direction an acid–base reaction lies?

What extent does the reaction goes to completion?

pKa’s are modified equilibrium constants that indicate theextent to which the acid (proton donor) reacts with water to

form conjugate acid and conjugate base.

Ka= acid dissociation constant

Ka= [H30] [HA] [ HA]

KaDissociationStronger acid

But, Ka is only for WEAK ACIDS

Weak acid vs Strong acid

Calculations:

Calculations:

Percent Ionization

Adjust the pH to ensure maximum water solubility (ionic form of the drug) or maximum solubility in non-polar media (un-ionic form).

Calculations:

Calculations

Calculations

Interpretation

• First, note that when pH = pKa, the compound is 50% ionized (or 50% un-ionized).

When the pKa is equal to the pH, the molar concentration of the acid equals the molar concentration of its conjugate base.

Application

• Phenytoin (HA acid; pKa 8.3) injection must be adjusted to pH 12 with sodium hydroxide to ensure complete ionization and maximize water solubility.

Application

• Tropicamide is an anticholinergic drug administered as eye drops for its mydriatic response during eye examinations.

• With a pKa of 5.2, the drug has to be buffered near pH 4 to obtain more than 90% ionization.

Problem Solving (on your own)1. Calculate the percent ionization and pH of solution of

acetic acid having the concentration of 1.30 M. Ka=1.8 e-5 pH= ionization= 

2. Calculate the percent ionization and pH of solution of acetic acid having the concentration of 0.13 M. pH= ionization= 

3. Calculate the percent ionization and pH of solution of acetic acid having the concentration of 0.013 M. pH= ionization= 

4. What happens to the % ionization as the solution becomes more concentrated? a) stay the same b) decreases c) increases 

Calculate (a) the pH and (b) percent ionization of 1.0 M acetic acid if the Ka is 1.86x10-5 at 20 °C.

Answers:1. 1.8 x 10^-5 = x^2/ 1.30-x 

x = 0.0048 M = [H+] pH = 2.3 ionization = 0.0048 x 100 / 1.30 = 0.37 

2. 1.8 x 10^-5 = x^2 / 0.13-x x = 0.0015 M pH = 2.8 ionization = 0.0015 x 100 / 0.13 = 1.18 

3. 1.8 x 10^-5 = x^2 / 0.013-x x = 0.00048 M pH = 3.3 ionization = 0.00048 x 100 / 0.013 = 3.7 

4. decreases

REMEMBER!!!!

• Drugs which are UNIONIZED, LOW POLARITY and HIGHER LIPID SOLUBILITY- easy to PERMEATE membrane.

• Drugs which are IONIZED, HIGH POLARITY and LOWER LIPID SOLUBILITY- difficult to permeate membrane.

Drug Distribution and pKa

• The pKa can have a pronounced effect on the pharmacokinetics of the drug.

• For HA acids, it is the parent acid that will readily cross non-polar membranes of capillary walls, cell membranes, and the blood-brain barrier.

• For BH acids, the unionized conjugate base (free amine) is the species most readily crossing the non-polar membranes

Drug Distribution and pKa

The drug first encounter the acidic stomach

HA acids with pKa’s of 4 to 5 will tend to be non-ionic and be absorbed partially

through the gastric mucosa.

Drug Distribution and pKa

The drug first encounter the acidic stomach

Amines (pKa 9–10) will be protonated (BH acids) in the acidic stomach and usually

will not be absorbed until reaching the mildly alkaline intestinal tract (pH 8).

COMPUTER-AIDED DRUG DESIGN:EARLY METHODS

• Steroidal hormones based on cortisone.

• Adrenergic drugs based on epinephrine.

• Opiate analgesics based on morphine.

• Antibiotics based on penicillin.

Cephalosporin and tetracycline.

Quantitativestructure–activity relationships

To quantify the effect of a structural change on a definedpharmacological response are used to:

(a) Predict biological activity in untested compounds(b) Define the structural requirements required for a good

fit between the drug molecule and the receptor(c) Design a test set of compounds to maximize the

amount of information concerning structural requirements for activity from a minimum number of compounds tested.

QSAR/ QSPR

• 1865 to 1870 by Crum-Brown and Fraser

-Gradual chemical modification in the molecular structure of a series of poisons produced some important differences

in their action.

QSAR

Biological response can be predicted

from physical chemical properties such as:

-Vapor pressure

-Water solubility

-Electronic parameters

-Steric descriptors

-Partition coefficients

QSPR

• Physical Properties of a drug

- Boiling point

- Dipole moment

WHY DO we QSAR?

QSAR and Drug Design

QSAR in drug companies perspective

QSAR

The most lethal compound in this assay was chlorpromazine, with a BR (LD100) of only 0.00000631 mmol; and the least active was ethanol, with a BR of 0.087096 mmol.

It takes about 13,800 times as many millimoles of ethanol than of chlorpromazine to kill 100% of the test subjects