k1k2DrugReceptorEffectDrug-Receptor ComplexLigand-binding domain Effector domain Drug(Ligand) Receptor interactionEffectD+R DRk1k2

FORCES INVOLVED IN BINDING OF DRUGS TO RECEPTORS.The driving force for the drug-receptor interaction can be considered as a low energy state of the drug-receptor complex,Where kon is the rate constant for formation of the drug-receptor complex, which depends on the concentration of the drug and the receptor koff is the rate constant for breakdown of the complex, which depends on the concentration of the drug-receptor complex as well as other forces.The biological activity of drug is related to its affinity for the receptor, i.e., the stability of the drug-receptor complex. This stability is commonly measured by how difficult is for the complex to dissociate, which is measured by its kd, the dissociation constant for the drug-receptor complex at equilibrium.

FORCES INVOLVED IN THE DRUG-RECEPTOR COMPLEX

Covalent bondingIonic interactions Ion-dipole and dipole-dipole interactions, Hydrogen bondingCharge transfer interactionsHydrophobic interactions, and Van der waals interactions

Development of Drug-receptor theory

a. Langley(1878): Intercounter of atropine with pilocarpine in salivary excretion.b. Langley(1906):Intercounter tubocurarine with nicotine in skeletal muscle receptive substance c. Ehrlich(1908): lock and key (receptor)d. Clark(1926-33): Acetylcholine on heart contraction. e. Dale, Ahlquist, Gaddum, Schild, Sutherland, et al.

Receptor theory was propounded by Alfred Joseph Clark, a theory of drug action based on occupation of receptors by specific drugs and the cellular function can be altered by interaction of the receptors with the drugs. The interaction between the drug (D) and receptor (R) is governed by the Law of mass action; the rate at which new DR complexes are formed is proportional to the concentration of D. This equation is derived from Langmuir absorption isotherm, the interaction of drug (D) with receptor (R) on forward or association rate constant (k1) and the reverse or dissociation (k2).It has been accepted that occupation of the receptor is essential but itself not sufficient to elicit a response; the agonist must be able to induce conformational change in the receptor.

THEORIES OF DRUG RECEPTOR INTERACTIONS

1. OCCUPATION THEORY: 2. RATE THEORY 3. THE INDUCED-FIT THEORY OF ENZYME-SUBSTRATE INTERACTION 4. MACROMOLECULAR PERTURBAION THEORY 5. ACTIVATION-AGGREGATION THEORY / TWO STATE MODEL OF RECEPTOR ACTIVATION Other theories The receptor cooperativity model The mobile receptor Model

Occupationtheory (1926) * Drugs act on independent binding sites and activate them, resulting in a biological response that is proportional to the amount of drug-receptor complex formed. * The response ceases when this complex dissociates. * Intensity of pharmacological effect is directly proportional to number of receptors occupied

D + R DR RESPONSE *Responseisproportionaltothefractionofoccupied receptors Maximalresponseoccurswhenallthereceptorsareoccupied Does not rationalize how two drugs can occupythe same receptor and act differently

Ariens responseisproportionaltothefractionof occupiedreceptorsand theintrinsicactivity Stephenson responseisaFUNCTIONofoccupancy maximumresponsecanbeproduced WITHOUT100%occupation,i.e.tissueshavesparereceptors Receptors are said to be sparespare for a given pharmacological response when the maximal response can be elicited by an agonist at a concentration that does not result in occupancy of the full complement of available receptors Spare receptors More receptors available than needed to elicit maximum responseallow maximal response without total receptor occupancy increase sensitivity of the systemAgonist has to bind only a portion of receptors for full effectEg: epinephrine

II. Rate theory (1961)The response is proportional to the rate of drug-Receptor complex formation.

Activation of receptors is proportional to the total number of encounters of a drug with its receptor per unit time.

According to this view, the duration of Receptor occupation determines whether a molecule is agonist, partial agonist of antagonist.

Does not rationalize why different types of compounds exhibit the characteristics they do.

III. THE INDUCED-FIT THEORY: (1958)States that the morphology of the binding site is not necessarily complementary with even the preferred conformation of the ligand. According to this theory, binding produces a mutual plastic molding of both the ligandand the receptor as a dynamic process. The conformational change produced by the mutually induced fit in the receptor macromolecule is then translated into the biological effect, eliminating the rigid and obsolete key and lock concept of earlier times Agonist induces conformational change responseAntagonist does not induce conformational change no responsePartial agonist induces partial conformational change - partial response

IV. Macromolecular perturbation theory:Suggests that when a drug-receptor interaction occurs, one of two general types of Macromolecular perturbation is possible: a specific conformational perturbationleads to a biological response (agonist), whereas a non specific conformational perturbation leads to no biologic response (Antagonist

V.Activation-Aggregation Theory Monad, Wyman, Changeux (1965) Karlin (1967) is an extension of the Macromolecular perturbation theorySuggests that a drug receptor (in the absence of a drug) still exists in an equilibrium between an activated state (Bioactive) and an inactivated state (Bio-inactive); Agonists bind to the activated state and antagonist to the inactivated state

V. THE TWO-STATE (MULTISTATE) RECEPTOR MODEL Was developed on the basis of the kinetics of competitive and allosteric inhibition as well as through interpretation of the results of direct binding experiments.It postulates that a receptor, regardless of the presence or absence of a ligand,exists in two distinct states: the R(relaxed, active or on) and T (Tense, inactive or off) states, which are in equilibrium with each other.Molecular level conceptual model of ReceptorThese models emphasize the fact that many receptors are not just simple macromolecules, which interact with a drug in hand in glove fashion. On the contrary, some receptors are extremely dynamic, existing as a family of low-energy conformers existing in equilibrium with each other. Other receptors have complex multi-unit structures, being composed of more than one protein; facilitatoryand inhibitory interactions exist between these subunits and may alter the drug-receptor interaction.Some receptors are not only dynamic in terms of their shape, but also mobile, drifting in the membrane like an iceberg in the ocean.

Two-state (Multi-state) Receptor ModelR 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 RPartial inverse agonists bind preferentially to RAntagonists have equal affinities for both R and R* (no effect onbasal 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.

Activation-Aggregation Theorycontd

Receptor is always in a state of dynamic equilibrium between activated form (Ro) and inactive form (To).In contrast to the classical occupation theory the agonist in the two-state model does not activate the receptor but shifts the equilibrium toward the R form.

Terminologies regarding drug receptor interactionAffinity

Efficacy

Potency

Ligand

Affinity: measure of propensity of a drug to bind receptor; the attractiveness of drug and receptor

Efficacy: Potential maximum therapeutic response that a drug can produce.

Potency: Amount of drug needed to produce an effect. Ligand: Molecules that binds to a receptor

ClassificationofLigands a. agonist b. partialagonistc. antagonist pharmacologicalvs.physiologicalvs.chemical pharmacologicalantagonists -competitive surmountable -noncompetitive

- Primary way for drug to produce an actionnon-specificreceptors neurotransmitters hormonesenzymestransport systemsion channels active transporters, e.g. uptake blockersDrug Receptor interactionTargets of drug action

DESENSITIZATION OF RECEPTORS- Receptor structure change

- Receptor inactivation (protein inhibitors, modifications)

- Down regulation of receptor byendocytosis or degradation

Receptor agonistAny drug that binds to a receptor and stimulates the functional activitiese.g.: adrenaline (epinephrine)CellEffect

AgonistDrugs that cause a responseDrugs that interact with and activate receptors; They possess both affinity and efficacyTypes Full agonists An agonist with maximal efficacy (response)has affinity plus intrinsic activityPartial agonists An agonist with less then maximal efficacyhas affinity and less intrinsic activity

Agonists differing in potency and maximum efficacy

PARTIAL AGONISTS - EFFICACYEven though drugs may occupy the same of receptors, the magnitude of their effects may differ.

[D](concentration units)% Maximal Effect0.010.101.0010.00100.001000.000.00.20.40.60.81.0Partial agonistFull AgonistPartial agonist

Receptor antagonistAny drug which can influence a receptor and produce no responsee.g.: propranolol (a beta blocker)epinephrinepropranololCompetitive Antagonist: both the drug and its antagonist compete for the same site of the receptorNon-competitive Antagonist: the drug and its antagonist do not compete for the same site

Antagonist Interact with the receptor Have affinity but NO efficacy Block the action of other drugs Effect only observed in presence of agonist

Types of AntagonistsCompetitive (Surmountable)decrease apparent PotencyNoncompetitive- Decrease apparent maximum efficacy

Competitive Antagonist competes with agonist for receptor

surmountable with increasing agonist concentration

displaces agonist dose response curve to the right (dextral shift)

Only affinity, no efficacy

Noncompetitive Antagonistdrug binds to receptor and stays boundirreversible does not let go of receptor

produces slight dextral shift in the agonist DR curve in the low concentration range

but, as more and more receptors are bound (and essentially destroyed), the agonist drug becomes incapable of eliciting a maximal effect

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