Physicochemical Properties of Drugs in relation to Drug Action Roselyn Aperocho Naranjo, RPh, MPH USPF, College of Pharmacy

Understanding the Modern Drug Design  Modern chemical techniques  Recent knowledge on disease mechanisms & receptor properties  Transportation of drugs in the body  Distribution of drug through different compartments  Metabolism of drugs in the liver and other organs  Structural characteristics of the receptor  Acid-base chemistry  Availability of the computer software that determines the three-dimensional shape of the receptor in order to design new molecules that will give optimum fit to the receptor

History: General Plant Source Specific Plants are selected Crude extracts Treatment for medical conditions

History: General Plant Source Specific Plants are selected Crude extracts Treatment for medical conditions Structure of Natural products Selective changes in the molecule

Selected molecules are changed due to:  Reduction of undesirable pharmacologic response of the drug (side-effect)  Obtain better drug response  Alter drug’s metabolism  Produce more cheaper and competitive supply of the product

Selected molecules are changed due to: Example: Morphine Cocaine Addiction effect Analgesic effect Local Anesthetic Effect CNS effects reduced enhanced reduced enhanced

Medicinal Chemistry in 1900’s  Phenothiazines – first synthesized as ANTIHISTAMINES - Careful investigation led to discover its TRANQUILIZING PROPERTY for the mentally ill patient.  Benzodiazepines – originated from an expected ring enlargement which resulted it to become a CNS RELAXANT

Overview receptordrugDrug-receptor complex Pharmacologic response

Overview

Drug Distribution  Oral Administration

Drug Distribution OOral Administration Solubility depends on: CChemical Structure SSize of particles SSurface area NNature of crystal form TType of tablet coating TType of tablet matrix

 Oral Administration Example:  CHLORAMPHENICOL  CHLORAMPHENICOL PALMITATE PRODRUG- inactive form but are easily metabolized in the liver to become active

Protein Binding

 Can affect the drug’s effective solubility, biodistribution, half-life in the body and interaction with other drugs.  Control access to certain body compartments  Prolong the drug’s duration of action  Limit the amount of drug available for biotransformation and interaction with specific receptor sites.

Tissue Depot  Fats in the body which can be a storage for drugs  The more Lipophilic the drug is, the more it will stay in the tissue  Example:  Thiopental

Drug Metabolism & Excretion

Statistical Prediction of Pharmacological Activity  Mathematical Model will explain many chemical processes Three goals in Drug Design Predict biological activity in untested compounds define the structural requirements required to fit to a specific receptor design a test set of compounds

QSAR  Proposed by Crum-Brown and Fraser in 1865 to 1870  Certain modification in the molecular structure of a poisonous compound produces an important differences in their action

QSAR

Topological Descriptors  Alternate method in describing molecular structure which is based on graph theory using the bonds that connects between atoms

Combinatorial Chemistry …to be continued Prepare ¼ sheet of paper for the quiz