med chem exam 2 - receptors and stereochemistry

receptor

a cellular macromolecule

drug

a chemical substance that interacts with a biological system to produce a pharmacological effect

signal transduction

process of converting extracellular signals into intracellular responses

key players in signal tranduction

- signaling molecules

- receptors

- signal transduction proteins and secondary messengers

- effector proteins

affinity

a measure of the tightness that a drug binds to the receptor

what is a drug's affinity a product of?

association and dissociation with receptor

potency

the concentration/dose range over which a drug produces a response

efficacy

the ability of a drug to turn receptor binding into a biological response

four main drug targets

- enzymes

- ion channels

- cell membrane carrier proteins

- receptors

four main receptors

- receptor tyrosine kinases

- ligand-gated ion channels

- intracellular receptors

- G-protein coupled receptors

enzyme inhibition/activation

drugs act within the cell by modifying normal biochemical reactions

drug-receptor interaction

drugs act on the cell membrane by physical and/or chemical interactions, usually through specific drug receptor sites

non-specific interactions

drugs act by physical or chemical interactions

intrinsic activity

a measure of the ability of a drug once bound to a receptor to generate a change in cellular activity

agonists vs antagonist

agonists: have affinity and intrinsic activity

antagonists: only have affinity

inter and intramolecular binding forces in drugs

hydrogen bonding, ionic bonds, van der waals forces, covalent bonds

what happens when a receptor binds to its ligand?

conformational change of receptor that leads to transmission of intracellular signal

what impacts binding specificity and affinity?

extent of molecular complementarity between ligand and receptor

agonism

a compound that mimics the effect of a natural substance; does not impact the rate of enzymatic catalysis

antagonism

a compound inhibits enzymatic action; slows down the rate of enzymatic catalysis

up/down regulation

tolerance/sensitivity at the cellular level may be the result of a change in the number of receptors due to changes in stimulation

dose-response curves

a plot of the log of drug concentration versus its effect

what impacts the shape of a dose response curve?

- affinity: position of the curve on the x-axis

- intrinsic activity: magnitude of the response

full agonist

a molecule that produces a max response (100% efficacy)

partial agonist

a molecule that produces a response lower than the maximum (50% efficacy)

inverse agonist

binds with an active receptor, stabilizes it, and reduces the activity (produce an inverse response) (-100% efficacy)

competitive antagonists

bind to active site of a receptor (can be displaced by high concentrations of the agonist)

what impact do competitive antagonists have on the dose-response curve?

shifts it to the right

noncompetitive antagonists

bind to allosteric binding of a receptor (cannot be overcome by higher concentrations of agonist)

what impact do noncompetitive antagonists have on the dose-response curve?

decreases the maximum efficacy

irreversible antagonists

chemically reactive compounds that bind to the receptor and react with its functional groups to form a covalent bond

what impact to irreversible antagonists have on the dose-response curve?

permanently reduce its maximum effect

effective dose (ED50)

dose at which 50% of the population shows a response

lethal dose (LD50)

dose at which 50% of the population dies

therapeutic index

an indication of a drug's safety

how do you calculate therapeutic index?

LD50/ED50

relationship between potency and ED50

agonist: inversely related

tolerance

decreased response to same dose with repeated exposure

what is the impact of tolerance on the dose-response curve?

shifts it to the right

sensitization

increased response to the same dose with repeated exposure

what is the impact of sensitization on the dose-response curve?

shifts it to the left

stereochemistry

the specific spatial arrangement of a compound's functional groups and carbon backbone in 3D space

constitutional/structural isomers

same molecular formula, but different connectivity

conformation isomers/rotamers

the non-identical spatial arrangement of atoms and groups in a molecule that result from rotating around a single bond

geometric isomers

structural features located in different relative positions in space (cis/trans)

what conformations can sugars adopt?

boat conformation (less stable)

chair conformation (more stable)

alpha sugar

anomeric carbon is axial

beta sugar

anomeric carbon is equatorial

chiral/tetrahedral stereogenic/asymmetric center

carbon atom is bonded to four different chemical groups

enantiomer

non-superimposable mirror images

diastereomers

non-superimposable, non-mirror images that contain two or more chiral centers

how to assign priority to atoms

higher priority = higher atomic number

S enantiomer

counterclockwise

R entantiomer

clockwise

what is the maximum number of stereoisomers of a molecule that can exist?

2^n (n = chiral carbons)

meso compound

one which is superimposable on its mirror image even though it contains chiral centers (achiral)

configuration

the particular arrangement of atoms in space that is characteristic of a given molecule

conformation

interconvertable by rotation about single bonds

eutomer

the most active isomer that delivers the desired activity

racemates

a mixture of the two left and right handed optical isomers in equal amount