DRUG RECEPTOR INTERACTIONS MEDICINAL CHEMISTRY-I [Type the abstract of the document here. The abstract is typically a short summary of the contents of the document. Type the abstract of the document here. The abstract is typically a short summary of the contents of the document.]
RUCHIT K. PADODARA ST 1 M.PHARM DEPT.PHARMACEUTICAL CHEMISTYRY
INTRODUCTION GENERAL CONSIDERATION THEORIES OF DRUG-RECEPTOR INTERACTION INTERACTION INVOLVED IN THE DRUG-RECEPTOR COMPLEX
INTRODUCTION When drug is taken, it travels through the body to a target site and elicits a pharmacological effect. The site of drug action, which is ultimately responsible for the pharmacological effect, is a receptor. Receptor are mostly membrane-bound proteins that selectively bind small molecules, referred to as ligands, that elicit some physiological response. Receptors are generally integral proteins that are embedded in the phospholipid bilayer of cell membranes. Drugs do not create new functions. They modify the inherent functions of the tissues or cell concerned. Hence,drug act by stimulating or depressing cellular activity; replacing deficient substance; causing irritation; or by killing or weakening the invading foreign organisms. Affinity: It is the ability of the drug to combine with the receptor.
Intrinsic
activity:It is the ability of the drug to activate (induce a conformational change in)the receptor consequent to receptor occupation. Agonist:have both affinity and maximal intrinsic activity. Comoetative antagonist:have affinity but no intrinsic activity. Partial agonist:have affinity but submaximal intrinsic activity. inverse agonist:have affinity but intrinsic activity with a minus sign.
GENERAL y
y
y
y
CONSIDERATION
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 drugreceptor complex, which depends on the concentration of the drug and the receptor, and 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.
Drug-receptor
complex
Koff INTERACTIONS INVOLVED IN THE DRUG-RECEPTOR
COMPLEX y The interactions involved in the drug-receptor complex are the same forces experienced by all interacting organic molecules and include 1. Covalent bonding 2. Ionic interactions 3. Ion-dipole and dipole-dipole interactions, 4. Hydrogen bonding 5. Charge transfer interactions 6. Hydrophobic interactions, and 7. Van der waals interactions Drug-receptor interaction involve one or more of the following types of bonding
y
Covalent bonding: The stability of this type of bond hardly permits the formation of an easily reversible drug-receptor complex. Only when the receptor is inactivated by an irreversible antagonist, there is the formation of covalent bond. E.g. acetylcholinesterases are irreversibly inactivated by a number of phosphate esters.
Ionic
interaction: For protein receptors at physipological pH basic groups such as the amino side chain of arginine,lysine provide a cationic environment.
Acidic groups, such as the carboxylic acid side chain of aspartic and glutamic acid, are deprotonated to give anionic groups. The antidepressent drug pivagabine is used as an example of molecule of a molecule that can hypothetically participate in an ionic interaction with an arginine residue. y
y
y
Ion-dipole and Dipole-dipole Interaction: As a result of the greater electronegativity of atoms such as oxygen, nitrogen, sulfur,and halogen relative to that of carbon, C-X bonds in drugs and receptors, where X is an elecronegative atom, will have an asymmetric distribution of elecrons;this produce electronic dipoles. These dipoles in a drug molecule can be attracted by other dipoles in the receptor, provided charges of opposite sign are properly alignd.Because the charge of dipole is less than that of an ion, a dipole-dipole interaction is weaker than an ion-dipole interation. In figure the insomnia drug
zaleplon(sonata)
Hydrogen
is used to demonstrate these interaction.
bonding: An imp. type of bonding between drugs and receptors is a weak and easily broken H-bond. Since many drugs contain hydroxyl,amino, carboxyl and carbonyl groups, they can form H-bonds with the receptors complex The reduced potency of many sulfur analogues of oxygen containing drugs has been attributed to the reduced ability of sulfur to form H-bond.
H-bond are a type of dipole-dipole interaction The interaction denoted as dotted line ±X-H····Y, to indicate that interaction between H and Y also occurs. Charge-Transfer Complexes :When a molecule that is a good electron donor comes into contact with a molecule that is a good electron acceptor, the donor may transfer some of its charge to the acceptor. This forms charge transfer complex, which, in effect is molecular dipole-dipole interaction. Electron donor contains electrons, E.g. alkenes, alkynes and aromatic moieties with electron donating substituents or groups that have a pair of nonbonded electrons, such as O,N and S moities. Acceptor groups contain electron deficient orbitals. E.g. alkenes, alkenes, alkynes and aromatic moieties with electron withdrawing substituents.
Hydrophobic
Van
Forces In the presence of a non-polar molecule or region of a molecule, the surrounding water molecule orient themselves and, therefore, are in a high energy state than when only the water molecule are around. When two nonpolar groups, such as a lipophilic group on a drug and a nonpolar receptor group, each surrounded by ordered water molecules become disordered in an attempt to associate with each other, this increase in entropy, therefore,result in a the free energy that stabilises the drugreceptor complex. This stabilisation is known as hydrophobic interaction. it is reversible type of bonding that liberates energy. der waals or london dispersion forces: Van der waals bonds exist between all atoms,even those of noble gases, and are based on polarizability or the induction of
asymmetry in the electron cloud of an atom by a nucleus of a neighbouring atom. Such forces operate within an effective distance of about 0.4 to 0.6 nm and exert an attractive force of less than 2 kj/mol. Threfore, they are often overshadowed by stronger interactions. Example of multiple of drug receptor interaction excluding van der waal interaction
RECEPTOR SITE THEORIES A)OCCUPATION y
y
THEORY:
Receptor occupancy theory, in which it is assumed that response emanates from a receptor occupied by a drug, has its basis in the law of mass action. The basic currency of receptor pharmacology is the dose± response curve, a depiction of the observed effect of a drug as a function of its concentration in the receptor compartment.
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Figure
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In general, the drug±receptor interaction is characterized first by binding of drug to receptor and second by generation of a response in a biological system. The first function is governed by the chemical property of affinity, ruled by the chemical forces that cause the drug to associate reversibly with the receptor.
y
shows a typical dose±response curve; it reaches a maximal asymptotic value when the drug occupies all the receptor sites.
B)RATE THEORY:
As an alternative to the occupancy theory, Paton proposed that the activation of receptors is proportional to the total number of encounters of the drug with its receptor per unit time. Therefore, the rate theory suggest that the pharmacological activity is a function of the rate of association and dissociation of the drug with the receptor,and not the number of occupied receptors. Each association would produce a quantum of stimulus. In the case of agonists, the rate of both association and dissociation would be fast. Where in case of antagonist rate of association would be fast,but the dissociation would be slow. THEORY OF ENZYME-SUBSTRATE C)THE INDUCED-FIT INTERACTION: The induced-fit theory of koshland was originally proposed for the action of substrates and enzymes. According to this theory the receptor need not necessarily exists in the appropriate conformation required to bind the drug. As the drug approches the receptor, a conformation change in the receptor could be responsible for the initiation of the biological response. According to the induced-fit theory, an agonist would induce a conformation change and elicit a response,but an antagonist would bind without a conformational change. D)M ACROMOLECULAR
PERTURBAION THEORY: According to this theory, Belleau proposed that interaction of small molecules of drug or a substrate with a macromolecule may lead either to
specific conformational perturbation(SCP)-would result in the specific response of an agonist i.e. the drug would posses intrinsic activity. Non-specific conformational perturbation(NSCP)no stimulant response would be obtained and an antagonist or blocking action may be produced. If a drug posses features which contribute to formation of both, an equilibrium mixture of the two complexes may result, which would account for a partial stimulant action. F)TWO STATE MODEL OF RECEPTOR ACTIVATION : y Proposed by monad-wyman-changeux y Two-state model of receptor activation proposes that, in the absence of the natural ligand or agonist, receptor exist in equilibrium(defined by equilibrium constant L;) between an active state (R*)which is able to initiate a biological response, and a resting state(R) , which cannot. y In the absence of a natural ligand or agonist,the equilibrium between R* and R define the basal activity of the receptor A drug can bind to one or both of these conformational states, according to equlibrium constants kd and k*d for formation of the drug receptor complex with resting(D·R) and active state (D·R*) respectively. y
y
y
Full
agonists alter the equilibrium fully to the active state by binding to the active state by and causing maximum response. Partial agonist preferentially bind to the active, but not to the extent that a full agonist does, so maximum response is not attained. Antagonists have equal affinities for both states(ie. have no effect on the equlibrium or basal activity and therefore, exhibit neither positive nor negative efficacy).
TYPES OF RECEPTORS Type
1: ligand-gated ion channels (also known as ionotropic receptors). These are membrane proteins with a similar structure to other ion channels, and incorporate a ligand-binding (receptor) site, usually in the extracellular domain.
Type
2: G-protein-coupled receptors (GPCRs). These are also known as metabotropic receptors or 7transmembrane-spanning (heptahelical) receptors.
They are membrane receptors that are coupled to intracellular effector systems via a G-protein. They constitute the largest family, and include receptors for many hormones and slow transmitters, for example the muscarinic acetylcholine receptor , adrenergic receptors and chemokine receptors
Type
3: kinase-linked and related receptors. This is a large and heterogeneous group of membrane receptors responding mainly to protein mediators. They comprise an extracellular ligand-binding domain linked to an intracellular domain by a single transmembrane helix.
Type
4: nuclear receptors.
These are receptors that regulate gene transcription. The term nuclear receptors is something of a misnomer, because some are actually located in the cytosol and migrate to the nuclear compartment when a ligand is present. They include receptors for steroid hormones, thyroid hormone, and other agents such as retinoic acid and vitamin D.
REFERENCES 1)Silver man R.B., The Or ganic Chemistr y of Dr ug Design and Dr ug action, Academic pr ess,2004,2nd Edition,123-143 2)K adam S.S., Pr inciples of Medicinal Chemistr y, Nir ali Pr ak ashan Pune,Volume2,44-48 3)Goodman & Gillman, Manual of phar macology and ther apeutics, Mcgr a w hill & Companies, Ne w Delhi, 25-26 4)Rang H.P. and Dale M.M,Phar macolog y,6th Edition, Elsevier Publisher ,2007,29-30
