Outline Chapter 2

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Chapter 2: Drug Design and Relationship of Functional Groups to Pharmacologic Activity

Introduction

Relationship Between Molecular Structure and Biologic Activity

Crum-Brown and Fraser - did studies on this relationship in 1869. Their initial hypothesis that one functional group = one biologic action was incorrect, but they demonstrated the concept that molecular structure influenced biologic activity.

Selectivity of Drug Action and Drug Receptors

When the action of acetylcholine was discovered, it was known that one chemical group could produce two different biologic effects.

Antagonists are molecules that block the effects of natural neurotransmitters (norepinephrine, histamine, dopamine, seratonin) and are usually larger in size than the native compound. Antagonists to peptide neurotransmitters and hormones (cholecystokinin, melanocortin) are usually smaller in size.

Both agonists and antagonists share structural components with the native compound and the neurotransmitter that they influence.

SARs: structure-activity relationships (underlying principle for medicinal chemistry)

Different functional groups can yield chemical entities with similar physiochemical properties (i.e. sulfanilamide antibiotics - sulfanilamide acts as an antagonist to PABA metabolism in bacteria because they share similar steric and electronic properties)

Biologic Targets for Drug Action

Physiochemical Properties of Drug

Acid-Base Properties of Drugs

Relative Acid Strength (pKa)

Predicting the Degree of Ionization of a Molecule

Water Solubility of Drugs

Hydrogen Bonds

Ionization

Predicting Water Solubility: The Empirical Approach

Predicting Water Solubility: Analytical/Quantitative Approach

Stereochemistry and Drug Action

Stereochemical Definitions

Disignation of Absolute Configuration

Stereochemistry and Biologic Activity

Easson-Stedman Hypothesis

Diastereomers

Conformational Isomerism

Drug Design: Discovery and Structural Modification of Lead Compounds

Process of Drug Discovery

Natural Product Screening

Drug Discovery via Random Screening of Synthetic Organic Compounds

Drug Discovery from Targeted Dedicated Screening and Rational Drug Design

Drug Discovery via Drug Metabolism Studies

Drug Discovery from the Observation of Side Effects

Refinement of the Lead Structure

Determination of the Pharmacophore

Alterations in Alkyl Chains: Chain Length, Branching, and Rings

Functional Group Modification: Bioisosterism

Bioisosterism

Classical and Nonclassical Bioisosteres

Classical

Nonclassical

Peptide and Protein Drugs

Physical and Chemical Properties of Peptides

Metabolism/Degradation of Peptide and Protein Drugs

Summary

Outline