Drug-Receptor Bonding Ionic : the strongest type of non-covalent bond. This results from the attraction of ions with opposite charges.

Ion-Dipole : results when there is an attraction between an ion and the partial charge of a dipole of the opposite polarity.

Dipole-Dipole : Here a partially positive atom in a dipole is attracted to a partially negative atom in another dipole. Hydrogen Bonding: A dipole-dipole interaction where on of the constituents is a hydrogen attached to a heteroatom.

Hydrogen bonds –Vary in strength –Weaker than electrostatic interactions but stronger than van der Waals interactions. –A hydrogen bond takes place between an electron deficient hydrogen and an electron rich heteroatom (N or O). –The electron deficient hydrogen is usually attached to a heteroatom (O or N). –The electron deficient hydrogen is called a hydrogen bond donor (HBD). –The electron rich heteroatom is called a hydrogen bond acceptor (HBA).

Hydrogen bonds HBAHBD –The interaction involves orbitals and is directional. –Optimum orientation is where the X-H bond points directly to the lone pair on Y such that the angle. between X, H and Y is 180 o.

Hydrogen bonds Examples of strong hydrogen bond acceptorsExamples of strong hydrogen bond acceptors - carboxylate ion, phosphate ion, tertiary amine. Examples of moderate hydrogen bond acceptorsExamples of moderate hydrogen bond acceptors - carboxylic acid, amide oxygen, ketone, ester, ether, alcohol. Examples of poor hydrogen bond acceptorsExamples of poor hydrogen bond acceptors - sulfur, fluorine, chlorine, aromatic ring, amide nitrogen, aromatic amine. Example of good hydrogen bond donorsExample of good hydrogen bond donors - Quaternary ammonium ion.

Lone pair electrons Water can act as an H-bond Donor or Acceptor Donates H Accepts H

Examples of H-bonding interactions

The Hydrophobic Effect : when two alkyl chains approach one another, water is extruded from the space in between them, resulting in an increase in entropy, and thus a decrease in energy.

Charge-Transfer Complexes : a lone pair of electrons is "shared" with a neighboring group that has considerable π character.

Van der Waals Forces : one carbon in a chain approaches another carbon on a neighboring chain, causing a perturbation known as an induced dipole. These opposite partial charges then attract one another.

 Drugs may also bind to receptors using covalent bonding. This may be a permanent bond, in which case the receptor or enzyme target is "killed", or it may be transient.

Drug Interaction with Receptor – NT binds to receptor NT = key Receptor = lock Lock & Key Model Receptor A NT

Receptor A NT

Receptor B Receptor A NT

Receptor B Receptor A NT Drug A Drug B

 - Adrenoceptor H-Bonding region H-Bonding region H-Bonding region Van der Waals bonding region Ionic bonding region

ADRENALINE  - Adrenoceptor

 - Adrenoceptor ADRENALINE

SALBUTAMOL

 - Adrenoceptor SALBUTAMOL

SALBUTAMOL

Dose = amount of drug administered to the patient Response = effect in the body produced by the drug Drug + Receptor  Drug-Receptor Complex  Response Dose Response Relationships

Response Log Drug Concentration [Molar] ED 50 KEY PARAMETERS 1. Dose required to produce any effect at all. 2. ED 50 = effective dose to produce 50% response 3. Dose required to produce maximum effect 4. Dose that produces a toxic response

Efficacy (or Intrinsic Activity) – ability of a bound drug to change the receptor in a way that produces an effect; some drugs possess affinity but NOT efficacy

Log Drug Concentration [Molar] ED Potency vs Efficacy Potency – how much drug is required to produce a certain effect. Response

Log Drug Concentration [Molar] ED Potency vs Efficacy Efficacy – how large an effect the drug produces. Response

 Agonists Drugs Drugs that interact with and activate receptors, they possess both affinity and efficacy. Agonist binds reversibly to the binding site Similar intermolecular bonds formed as to natural messenger Induced fit alters the shape of the receptor in the same way as the normal messenger Receptor is activated Agonists are often similar in structure to the natural messenger E Agonist R E Agonist R Signal transduction AgonistR Induced fit

 Antagonists Drugs Drugs that interact with receptors but do not change them. They have affinity but no efficacy. Two types: Competitive (reversible) antagonists. Non competitive (irreversible) antagonists.

Competitive (reversible) antagonists Competitive (reversible) antagonists Antagonist binds reversibly to the binding site Intermolecular bonds involved in binding. Different induced fit means receptor is not activated No reaction takes place on antagonist. Level of antagonism depends on strength of antagonist binding and concentration. Messenger is blocked from the binding site. Increasing the messenger concentration reverses antagonism. An ER M An R

 Non competitive (irreversible) antagonists Antagonist binds irreversibly to the binding site. Different induced fit means that the receptor is not activated. Covalent bond is formed between the drug and the receptor Messenger is blocked from the binding site. Increasing messenger concentration does not reverse antagonism. X OH X O Covalent Bond Irreversible antagonism

 Non competitive (reversible) allosteric antagonists Antagonist binds reversibly to an allosteric site. Intermolecular bonds formed between antagonist and binding site. Induced fit alters the shape of the receptor. Binding site is distorted and is not recognised by the messenger. Increasing messenger concentration does not reverse antagonism. ACTIVE SITE (open) ENZYME Receptor Allostericsite Binding site (open) ENZYME Receptor Induced fit Binding site unrecognisable Antagonist

Stereochemical Aspects in Drug Receptor Interaction – Drug molecules must generally interact with biomolecules in a very specific way to elicit a pharmacological response. – Biomolecules are chiral, they often discriminate between isomers of a given drug molecule. – The stereochemistry of a drug can impact its ability to bind to its target.

The reason for chiral recognition by drug receptors is a three-point interaction of the agonist or substrate with the receptor or enzyme active site, respectively.

Examples:  Only the (-) enantiomer of epinephrine has the OH group in the binding site, and therefore has a much more potent pressor activity.

▪ Enantiomers interact with living systems in very different ways and results for example in: − Different smell Olfactory sensors are chiral

− Different taste Aspartame (S,S)(R,R) Bitter!!160 Times Sweeter than Sugar Taste buds are chiral

− Different drug effects Biomolecules, thus, can discriminate between enantiomers (isomers) of a given drug molecule. The net result is same or different pharmacologic/ pharmacokinetic/ toxicologic activities

Biological Discrimination =>

THALIDOMIDE: DISASTROUS BIOLOGICAL ACTIVITY OF THE “WRONG” ENANTIOMER −In the 1960’s thalidomide was given as racemic mixture (RS) to pregnant women to reduce the effects of morning sickness (Nausea and vomiting of pregnancy). −This led to many disabilities in babies and early deaths in many cases. The photographs are both from ‘Molecule of the Month’ at Bristol University:

− Later found that only the R-isomer can be used safely − In 1998 thalidomide has been approved by FDA to reduce the immune system’s inflammatory response in a host of illnesses, including arthritis, lupus, cancer, leprosy, and AIDs.

(S)-Fluoxetine(R)-Fluoxetine Copyright© 1999, Michael J. Wovkulich. All rights reserved. − The pure S enantiomer prevents migraines. − A racemic mixture of fluoxetine (sold as the antidepressant Prozac) doesn’t prevent migraines. L-Dopa Anti-Parkinson’s disease drug D-Dopa Biologically inactive has serious side effects

Ketoprofen R(-) ketoprofenS(+) ketoprofen devoid of pharmacological activity not biologically inert: toxic, increases risk of gastric disease powerful analgesic with anti-inflammatory activity with reduced toxicity

Likewise, cis/trans isomers of cyclic compounds, or Z/E isomers of alkenes are also expected to have different binding potency and therefore also different biological activity.

According to this theory, the "right" isomer is called the eutomer. The "wrong" isomer is called the distomer. The ratio of the activities of the eutomer and the distomer is called the eudismic ratio, and converting the equation to log form affords the eudismic index, EI.

Acetylcholine may interact with the muscarinic receptor of postganglionic parasympathetic nerves and with Acetylcholine esterases in the fully extended confirmation and in a different more- folded structure with the nicotinic receptors at ganglia and at neuromuscular junctions. – Gauche conformer = muscarinic – Anti conformer = nicotinic

Conformation is a spatial arrangement of a molecule of a given constitution and configuration.

Proteins are built from L-amino acids, which implies that enzymes - the catalysts of nature - are chiral Consequently, most biomolecules are chiral (sugars, DNA, proteins, amino acids, steroids) Also, receptors (drug, taste, biopharmaceuticals, agrochemicals) are chiral and the natural ligand to a receptor is often only one specific enantiomer This is why mirror image molecules can have radically different activities (effectivity, toxicity, taste) in the body. COOH R R NH 2 H H C C Life is Chiral

–Enantiomers: Optical isomers which are mirror images –Diastereoisomers: Optical isomers which are not mirror images –Racemates: Mixture of equal parts of enantiomers IsomerRelative Activity D (-) Pseudoephedrine DL Pseudoephedrine L (+) Pseudoephedrine L (+) Ephedrine DL Ephedrine D (-) Ephedrine Pressor activities of ephedrines - Ephedrine (more active) Stereochemistry