Outline Chapter 2

Chapter 2: Drug Design and Relationship of Functional Groups to Pharmacologic ActivityIntroductionRelationship 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 ActionPhysiochemical Properties of DrugAcid-Base Properties of DrugsRelative Acid Strength (pKa)Predicting the Degree of Ionization of a MoleculeWater Solubility of Drugs Hydrogen Bonds IonizationPredicting Water Solubility: The Empirical ApproachPredicting Water Solubility: Analytical/Quantitative ApproachStereochemistry and Drug ActionStereochemical Definitions Disignation of Absolute ConfigurationStereochemistry and Biologic Activity Easson-Stedman Hypothesis Diastereomers Conformational IsomerismDrug Design: Discovery and Structural Modification of Lead CompoundsProcess of Drug DiscoveryNatural Product ScreeningDrug Discovery via Random Screening of Synthetic Organic CompoundsDrug Discovery from Targeted Dedicated Screening and Rational Drug DesignDrug Discovery via Drug Metabolism StudiesDrug Discovery from the Observation of Side EffectsRefinement of the Lead Structure Determination of the Pharmacophore Alterations in Alkyl Chains: Chain Length, Branching, and RingsFunctional Group Modification: Bioisosterism Bioisosterism Classical and Nonclassical Bioisosteres  Classical  NonclassicalPeptide and Protein DrugsPhysical and Chemical Properties of PeptidesMetabolism/Degradation of Peptide and Protein DrugsSummary

Outline