Organic Chemistry in Pharmacy

physicochemical properties

How functional groups present on a molecule affect acid base properties

functional groups

chemically distinct groups of connected atoms which are important determinants of drug properties

Hydrophilic

water loving

Hydrophobic

Water fearing

lipophilic

fat loving

lipophobic

fat hating

optical activity

the ability of a chiral molecule to rotate plane-polarized light

Enantiomers

isomers that are mirror images of each other

electronic effects

how groups affect electronic environment within/between molecules

Solubility Effects

to what extent does the drug dissolve in aqueous or organic media?

steric effects

how does the size and shape of the molecule impact its in vivo activity

intermolecular interactions

interactions between molecules

intermolecular forces, strongest to weakest

ion-ion, ion-dipole, dipole-dipole (Hydrogen bonding apart of), van der waals

ion-ion

(+,-) very strong

ion-dipole

is an ion bonded with a polar molecule

dipole-dipole

between polar molecules

hydrogen bonds

weak attraction between a hydrogen atom and another atom

van der Waals forces

a slight attraction that develops between the oppositely charged regions of nearby molecules

ADRs

adverse drug reactions

DIs

Drug interacts

between two or more drugs or drugs with food, beverages, or supplements

In vivo

occurring within the body

disposition

the measure of the absorption, distribution, metabolism, and excretion of a chemical or substance

SN2

requires a strong nucleophile, adds antiperiplanar switching stereochemistry

Hydrolysis

Breaking down complex molecules by the chemical addition of water

Oxidiation- reduction

is a reaction that involves the transfer of electrons from one species to another

Conjugation

are overlapping P orbitals

Double bonds either cis or trans

Pharmacophore

essential functional groups of a drug

Which organic reactions occur in vivo and which cannot

nucleophilic addition can occur

Electrophilic aromatic substitution cannot occur

Organic oxidation/reduction reactions-- can occur

specifically when the agent is reduced

Pericyclic runs: cannot occur

What is the charged state for acidic groups based on pH?

Acidic groups become positive

What is the charge state for basic groups based on pH?

They become positive

What is the charge state for carboxylic groups based on pH?

Negative

What is the charged state for nitrogen heterocycles/amines based upon pH?

Become positive

What is the charged state for phenyls and amides based upon pH?

Neutral

In vivo reactions of drug

nuc addition

oxid/red (Mostyly esters)

SN2

Conjugation

How do drugs react in the body?

They react two ways

forming new bonds (covalent or ionic | Using pairs or single electrons)

breaking covalent bonds (Results in a again, loss, or split of electrons)

what should be taken into consideration when comparing drug FGs?

water/lipid solubility

mech of interactions (IMFs!!)

pharmacokinetics (ADME)

ADRs, DIs

suitability for specific therapeutic situation

what FG can provide the initial ionic bond to active site

carbox acid (loses H = polar = very reactive)

what FG can incorporate binding affinity by interactions w hydrophobic site

phenyl/aryl

non C or non H atom?

hetero atom

what are & describe the parts that a FG is generally composed of

heteroatoms (could include C or H too)

pharmacophore - essential FG

auxophore - nonessential group but enhance activity/modify kinetics

cyclic molecule that contains atoms other than C

aromatic heterocycle

any ring that contains N + ex of where found in vivo

nitrogen heterocycle, ie nucleic acids

benzyl vs phenyl/aryl (carbocycles differntiation)

benzyl = ring + —CH2—

phenyl = ring w any side chains

what is optical activity in a molecule an indication of

molecular asymmetry/ atom in molecule is chiral

why is it important to differentiate between drug enantiomers

each configuration may have different chemical activity

ie 1 config can be toxic like S-thalidomide

why cant a pure drug enantiomer be adminstered

may react in body = change chirality = become toxic form

more active/potent enantiomer of a drug is called..?

+ root names that indicate this property?

enantiopure drug

-ar-, -es-, dextro-, levo-

3 major determinants for pharmacology/FGs (PK & PD)

electronic effects

solubility effects

steric effects

rxns that occur in vivo

nuc addition, organic oxid/red, hydrolysis (mostly esters), substitions (SN2, conjugation)

why cant most chem rxns work in vivo

body is mostly water

org chem involves P orbital rxns = too high E & heat = no safe

what are the only possible mechanisms of action a drug can have in body to cause its effects

organic chem (mostly covalent) rxns OR most often, IMF interactinos

how do drugs react in vivo

form or break bonds, IMFs

2 main considerations when testing drug effects in vivo

stability - whether drug breakdown/react quickly

if stable (for secs, min, days), then what happens to drug? if unstable, then biotransforms = inactive = excreted

disposition - what happens to drug based on chem property

where stable drug ends up based on solubility (water, fat)

how determine protein stability

it depends (on amino acid, sterics, how adminstered)

why cant carbocation, carbcanion, acyl chloride exist in vivo

too reactive

Determine stability/deposition of glycine

glycine = amino acid = hydrophilic + stable, ionized in most tissues

Determine stability/deposition of pyrimidine

pyrimidine = N heterocycle in DNA = stable + hydrophilic

Determine stability/deposition of 3-hexanone

3-hexanone = stable + lipophilc

determine stability/deposition of ethyl propionate

common FGs on drugs

alcohol, ketone, aldehyde, carbox acid, amine/N-containing, halide

what rxn is common in liver

oxidation/reduction (ie -COOH → -CO)

amides = acid or base?

neither/neutral always bc has acidic & basic properties that cancel eachother out

strongest base?

OH-

how determine which drug will be most soluble in vivo

compare # of polar/nonpolar FGs

SAR?

structure-activity relationships

what can increase drug-receptor affinity

electronic effect - drug has electron donating group = inc polarity/reactivity

steric effect - smaller FG = easier rxn

solubility effect - more soluble in body bc more polar = more reactive = stronger affinity

what FG can be hydrolyzed in vivo

ester

affinity

strength of drug-receptor binding interaction

potency

dose/amount needed to produce effect from binding (comparison of ED50s of drugs that bind to same receptor)

ED50

dose of drug producing half the maximum response

efficacy

change that occurs as a result of drug binding to receptors (drugs ability to cause physiological change, relationship bw size/strength of response & occupancy of receptor)

rank most basic to least basic: amide, carbox acid, amine

amine, amide, carbox acid

a drug that binds a receptor with higher affinity will have a ____________? Kd than a drug that binds w lower affinity

smaller

what func group is charged at physiological pH

phosphate (DNA)