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Chemical structure and Bioactivity (Structure Activity Relationships…
Chemical structure and Bioactivity
Structure Activity
Relationships (SAR)
a minor replacement of -S- of antipsychotic Chlorpromazine by -CH2-CH2- produces the antidepressant Clomipramine
Very different structurally Morphine and Enkephaline have the same action
Bioesters
groups that have similar effects on
drug molecule as the native group
useful for attempting chemical changes to drug so as to retain desirable biological action, but reduce toxicity
Apolar drugs
high lipophilicity
will cross lipid membrane barriers to reach target
Polar drugs
pKa renders them charged at physiological pH, resulting in restricted passage across membranes
Lipid solubility
Measured by determining the partition coefficient (P) of a drug between water and an organic solvent
specific constituent groups (e.g. methyl group) will make approximately constant contributions to P
Hansch substituent constants (Pi) allow the prediction of the lipid solubility of series of structurally derivative compounds
Drug ionisation
Ionisation state can affect various physiochemical properties of a drug via H-bonding and charge distribution
Pharmacokinetics
drug solubility and membrane penetration
affect the drug absorpotion and distribution
liphophilicity affects the distribution
Pharmacophore
conformation and orientation of intermolecular interactinos
Bioavailability
susceptibility to metabolism
in situ stability of a drug affects its potency
Esters and N-substituted amides have
similar shapes and electron distributions
Prodrugs
employing the native metabolism to activate the prodrug
Dipvalolyladrenaline is metabolised and
activated by esterase in the eye
Pivampicillin is better absorbed orally than ampicillin to which it is converted following absorption
Amides are metabolised more slowly, so the O to N substitution may increase stability to increase potency or T1/2 if the nature of the activity remains the same
Procaine
change of the ester group to an amide group (procainamide) changes activity from a local anaesthetic to an antiarythmic
Acetylcholine Analogues
Metacholine
reduced nicotinic action
reduced acetylcholinesterase sensitivity
addition of 1 methyl group to one of acetylcholine carbons
Cholinesterase is very effective at breaking down ACh.
To extend the cholinergic activity, this mechanism needs to be circumvented
Carbachol
nicotinic and muscarinic activity
reduced acetylcholinesterase senstivity
Chatecholamines
Role of size of the N-substituent
larger substituents increase
B-adrenoceptor activity but reduce A-adreonceptor activity
decrease sensitivity to MAOs
Isoprenaline
Salbutamol
decrease COMT sensitivity
Salbutamol
Bisquaternary Ammonium Blockers
Hexamethonium (6CH2 groups separating
ammonium ions) => Ganglion blocker
effects of the chain length
Decamethonium (10 CH2 groups) => neuromuscular blocker
Suxamethonium (10 atoms between
ammonium ions) => depolarising NMJ blocker
Chemical features
of importance
Lipophilicity
Pharmacokinetics and interaction with target
Anaesthetics
Charge
Pharmacokinetics and interaction with target
e.g. v.g. channel block
Shape
complementarity
with target
lock and key
stereospecificity
Molecular interactions
long range
Ionic
Ionic-Dipole
Dipole-Dipole
short range
Hydrogen bonds
Charge transfer interaction
Hydrophobic interactions
Van der Waals attraction
Pharmacophore
for strong interaction by short
range forces, molecules have
to fit together, which is infulenced by
molecular size
shape
electron distribution
sum of interactions determines effectiveness of drug binding
pharmacophore - combined Steric (size/shape) and Electronic (charge/hydrophobicity) features of a drug to achieve optimal supramolecular interaction with targe to affect function
Chemical properties -> Drug action
Pharmacokinetics
Water solubility
Lipid solubility
Balance needed between hydro- and lipophilicity for drig to pass alternately between water and lipids to get to the target and not get trapped in either phase
Pharmacodynamics
Pharmacophore
Quantative SAR
mathematical relationship between the biological
activity and molecular properties
Hansch equation
C - minimum effective dose
factors
Electronic parameters
charge/ionisation
Hammet substituent constant (sigma)
Steric parameters
shape
Taft steric term (Es)
Liphophilicity
Hansch constituent constant (P)
Drug delvelopment
the old way
trial and error
the new way
computer stimulations
use of 3D modelling on structural databases