Medicinal Chemistry Applications

potency/affinity

ability of the drug to interact with the drug target at the lowest concentration possible

requires strong attraction of drug molecule toward the target

helps with selectivity

helps with ease of optimizing bioavailability

selectivity

to optimize a drug, need this against the target you want

requires weaker attraction to all other proteins in the body

big enough difference in potency toward the target you want versus all the other proteins in the body

prevents unwanted off-target (side) effects

bioavailability

fraction of the dose that gets to the circulation

helps improve drug concentration at the site of action

solubility in aqueous GI tract requires good reversible binding to water

absorption, transcellular diffusion requires interactions with lipids

interactions of the drug with the target

hydrogen bonding, aromatic ring interactions, van der waals, ionic/electrostatic

interaction of the drug with itself (not water)

hydrophobic (lipophilic) interactions

makes tiny micelles where the drug interacts with itself

also called desolvation to break up the micelles

what are the h-bond donors?

hydrogens, which are attached to N or O

what are the h-bond acceptors?

non-bonded electrons in O, N

aromatic ring interactions

parallel staggered, T-shaped

staggered to center (-) interacts with outer (+)

pi-cation interaction

type of aromatic ring interaction

uses the (+) of common ionized base to interact with (-) of center

pi-amide interaction

type of aromatic ring interaction

uses the pi double bond in an amide to interact with the (-) of the center

ionic interaction types

fully charged and partial charges (dipoles)

van der waals interactions

shape complimentary, drug atoms close enough to protein atoms so that their electron clouds attract

most common are from CH with CH

easily confused with hydrophobic interactions

adrenergic receptors

natural ligands (agonists) are epinephrine and norepinephrine for all of the adrenergic receptors

dopamine also happens to activate them but with less potency

what are the two categories of adrenergic receptors?

alpha 1 and alpha 2, beta 1 and beta 2

beta 2 agonists

example: anti-asthma drugs

they dilate the airways (bronchodilators)

beta 1 blockers (antagonists)

lower heart rate and dilate vasculature

what regions of the catecholamine structure contribute to selective binding recognition to distinguish the 4 receptors?

amino, aromatic ring, catechol hydroxyl

what are the catecholamines?

epinephrine, norepinephrine, dopamine

what binding interaction needs to happen for something to be a beta 2 agonist?

hydroxyl hydrogen binding needed at the catechol OH

molecule binds to Gs protein and initiates the receptor signal

functional groups leading to selectivity of beta-blockers

N-alkyl region (t-butyl) (favors B2)

large group below ring (favors B1)

rings with no additional attachments (not selective for any adrenergic receptor)

B2 agonist examples

albuterol, terbutaline, salmeterol