INTERACTION OF DRUG AND RECEPTOR & ITS THEORY

MEDICINAL CHEMISTRY
Semister # 2- 2012

Contents INTRODUCTION INTERACTION INVOLVED IN THEDRUG-RECEPTOR COMPLEX THEORIES OF DRUG-RECEPTOR INTERACTION REFERENCES

INTRODUCTION
1878 Langley Study of antagonistic action of alkaloids on cat salivary flow suggests the compounds interacted with some substance in the nerve endings 1897 Ehrlich Side chain theory - Cells have side chains that contain groups that bind to toxins - termed receptors 1906 Langley Studying antagonistic effects of curare on nicotine stimulation of skeletal muscle Concluded receptive substance that received stimulus, and by transmitting it, caused muscle contraction Two fundamental characteristics of a receptor: 1. Recognition capacity - binding 2. Amplification - initiation of response Binding produces a conformational change Conformational change translated into functional change in protein (Stimulus) Ionic conductance Binding/release of G-proteins Change in conductance/enzymatic activity translated into physiologic changes (response) Agonist activates (turns on) receptor. Can be full or partial. Antagonist blocks response of an agonist. Inverse agonist deactivates (turns off) a constitutively active receptor. To effect a certain response of a receptor, design an agonist (or partial agonist). To block a particular response of a natural ligand of a receptor, design an antagonist (or partial agonist). To produce the opposite effect of the natural ligand, design an inverse agonist.

Affinity and efficacy are not directly coupled, but a compound can have great affinity but poor efficacy (and vice versa). A compound can be an agonist for one receptor and an antagonist or inverse agonist for another receptor. A full or partial agonist displays positive efficacy. An antagonist displays zero efficacy. A full or partial inverse agonist displays negative efficacy.

Table 3.1

Neurotransmitter

Agonists

Antagonists

CH3O N NH2 NH 2 HN N Histamine N HN N CH 3 NH 2 N N Pyrilamine

N(C H 3)2

Agonists - often structural similarity

Cl

N CH 3

Chlorcyclizine

Antagonists - little structural similarity

OH HO HO NHCH 3 Epinephrine HO

O OH NHCH 3 MeO MeO N N NH 2 Prazosin N N O

How can agonists and antagonists bind to same site and one show response, other not?

Figure 3.14

Agonist

antagonist

enantiomer

All naturally-occurring chemicals in the body are agonists

Most xenobiotic are antagonists Drugs that bind to multiple receptors side effects
Drug Action at Receptors
Neurotransmitters and Hormones both interact with receptors message received cellular response internal chemistry adjusted biological response

How can drugs play a role? Consider problematic states: Too many chemical messengers released A drug could be developed to block receptors (antagonist) Too few chemical messengers released A drug could serve as a replacement messenger (agonist)

Design of Agonist Requires knowledge of the endogenous messenger requirements: correct binding groups correct position of binding groups correct size for binding site similarity to structure of endogenous messenger

Binding Groups Similar characteristics to endogenous substrate H-bonds vdw forces ionic

Position of Binding Groups The rest of the molecule is a framework to hold binding groups in correct position

Size and Shape Binding Groups and Framework may be ok but other groups on the drug may prevent drug from binding (i.e., cant get close enough)

Design of an Antagonist At the Binding Site: the designed structure must have the correct shape to bind at site of action. binds but NO change in receptor shape (if agonist causes change) binds and causes shape in receptor (if agonist causes NO change)

Forces Involved in a Drug-Receptor Complex Covalent Bonds Ionic Interactions Ion-Dipole & Dipole-Dipole Interactions Hydrogen Bonds Charge-Transfer Complexes Hydrophobic Interactions Van der Waals Forces Covalent Bonds Extremely strong bonds (-40 to -110 kcal/mol) Less common for drug-receptor complexes (except for labeling experiments) More common for enzyme or DNA interactions with drugs. Ionic Interactions (at physiological pH; 7.4) Mutual attraction of opposite charges Basic groups such as amines (from arginine, lysine, and histidine) Acidic groups such as carboxylic, phosphoric, sulfonic acids (glutamic and aspartic acid) ~ -5 kcal/mole (depends upon magnitude of charge and distance) and may be enhanced by additional interactions.

Ion-Dipole & Dipole-Dipole Interactions Dipoles result from bonding between two atoms of different electronegativities. Dipoles in a drug can be attracted by ions or by other dipoles in the receptor.

Dipole-dipole interactions are weaker than ion-dipole interactions b/c the charge is generally less than that of an io

 -1 to -7 kcal/mol

Hydrogen Bonds Dipole-dipole interactions involving X-H groups (X is electronegative) and other electronegative groups (Y). Y = N, O, F May be intramolecular or intermolecular ~ -3 to -5 kcal/mol

Charge-Transfer Complexes Some charge from an electron donor is transferred to a good electron acceptor. Similar to dipole-dipole interactions. Electron donors contain electrons (alkenes, alkynes, and aromatic groups with electron-donating groups such as O, N, and S)

 Electron acceptors contain electron-deficient-orbitals (alkenes, alkynes, and aromatic groups with electron-withdrawing substituents, or weakly acidic protons). In a receptor, Donors = tyrosine (aromatic) or carboxylates (asparate or glutamate). In a receptor, Acceptors = cysteine, Acceptor & Donor = histidine, tryptophan, asparagine ~ -1 to -7 kcal/mol Example: may be involved in the intercalation of planar antimalarial drugs such as chloroquinone into parasitic DNA (see figure below)

Hydrophobic Interactions Hydrophobic groups cause water molecules to orient themselves around them. Therefore, there is higher order or energy in such cases. When two hydrophobic groups approach each other, the highly ordered water molecules become less ordered and the Increase of entropy results in a decrease of free energy. This decrease in free energy is the hydrophobic interaction. Therefore, not an attractive force. ~ -0.7 kcal/mol per CH2- CH2 interaction.

Van der Waals Forces Temporary dipoles from drug or receptor induce opposite dipoles in the approaching molecule. Significant with close surface contact of atoms from each source. More significant in the cases of molecular complementarity ~ -0.5 kcal/mol each atomic interaction

THEORIES OF DRUG-RECEPTOR INTERACTION

Occupancy Theory (1926) Intensity occupied Does not rationalize how two drugs can occupy the same receptor and act differently of pharmacological effect is directly proportional to number of receptors

Drug-Receptor Theories
Occupancy Theory (1926)
Intensity of pharmacological effect is directly proportional to number of receptors occupied Does not rationalize how two drugs can occupy the same receptor and act differently

Rate Theory (1961)

Activation of receptors is proportional to the total number of encounters of a drug with its receptor per unit time. Does not rationalize why different types of compounds exhibit the characteristics they do.
drug + receptor kon koff drug-receptor complex

Kd =

[drug][receptor] [drug-receptor complex]

Induced Fit Theory (1958)

Agonist induces conformational change - response Antagonist does not induce conformational change - no response Partial agonist induces partial conformational change partial response

Figure 3.16

Activation-Aggregation Theory
Monad, Wyman, Changeux (1965) Karlin (1967) Receptor is always in a state of dynamic equilibrium between activated form (Ro) and inactive form (To). Ro
biological response

To
no biological response

Agonists shift equilibrium to Ro Antagonists shift equilibrium to To Partial agonists bind to both Ro and To Binding sites in Ro and To may be different, accounting for structural differences in agonists vs. antagonists

Two-state (Multi-state) Receptor Model

R and R* are in equilibrium (equilibrium constant L), which defines the basal activity of the receptor. Full agonists bind only to R* Partial agonists bind preferentially to R* Full inverse agonists bind only to R
Kd D R Kd* D + R resting L D + R* active

Figure 3.17

D R*

Partial inverse agonists bind preferentially to R Antagonists have equal affinities for both R and R* (no effect on basal activity) In the multi-state model there is more than one R state to account

for variable agonist and inverse agonist behavior for the same receptor type.

Drug and Receptor Chirality

Drug-Receptor Complexes
Receptors are chiral (all L-amino acids) Racemic mixture forms two diastereomeric complexes
[Drug]R + [Drug]S + [Receptor]S

[Drug]R [Receptor]S + [Drug]S [Receptor]S

Have different energies and stabilities

Receptor Interaction
H HO HO CH2NH2CH3 + OH HO HO H OH CH2NH2CH3 +

Ar

Ar

R-(-)-epinephrine

S-(+)-epinephrine

Figure 3.20

Ligand enantiomers cannot be distinguished with only two points of attachment.

Three-point attachment concept

H HO HO CH 2NH 2CH 3 + OH HO HO H OH CH 2NH 2CH 3 +

Ar H

Ar H

R-(-)-epinephrine

S-(+)-epinephrine

Figure 3.21

Receptor needs at least three points of attachment to distinguish enantiomers of a ligand.

References:
1. The Organic Chemistry of Drug Design and Drug Action by Richard B. Silverman Ph.D Organic Chemistry, 2nd Edition, Chapter 3 Receptors. 2. Principles of Organic Medicinal Chemistry by Rama Nao Nadendla. 3. Foye's Principles of Medicinal Chemistry by David A. Williams, William O. Foye, Thomas L. Lemke 4. An Introduction to Medicinal Chemistry by GRAHAM L. PATRICK. OXFORD UNIVERSITY.