RECEPTORS:STRUCTURAL & FUNCTIONAL FAMILIES OF RECEPTOR PRESENTED BY: KULKARNI AMOUGH ANIL M. Pharm (1 st year) Department of Pharmacology. KLES College of Pharmacy, Hubballi

 INTRODUCTION  NATURE OF RECEPTORS  COMMON TERMS USED UP  DRUG-RECEPTOR THEORY  SOME BASIC EVIDENCES  CLASSIFYING RECEPTORS  ACKNOWLEDGEMENT

 'Receptor' is used to denote any macromolecule/binding site with which a drug/signal molecule has to combine in order to elicit its specific effect, but itself has no other function.  'Ehrlich' summed it up thus: 'Corpora non agunt nisi fixata' ('A drug will not work unless it is bound').  It form a key part of the system of chemical communication that all multicellular organisms use to coordinate the activities of their cells and organs.  Specificity is reciprocal.

NATURE

TERMS USED IN DRUG-RECEPTOR INTERACTION  AGONIST  INVERSE AGONIST  ANTAGONIST  PARTIAL AGONIST

HOW DO DRUGS/SIGNAL MOLECULE WORK? Cell Membrane Unbound Endogenous Activator of Receptor Inactive Receptor Extracellular Compartment Intracellular Compartment

HOW DO DRUGS/SIGNAL MOLECULE WORK? Cell Membrane Bound Endogenous Activator of Receptor Active Receptor Extracellular Compartment Intracellular Compartment Cellular Response

AGONIST /ANTAGONIST

PARTIAL/INVERSE AGONIST Dose % Effect

DRUG-RECEPTOR INTERACTION THEORY  RECEPTOR OCCUPATION THEORY  THE TWO-STATE RECEPTOR MODEL

RECEPTOR OCCUPATION THEORY  Clark (1937) propounded the theory of drug action based on occupation of receptors by specific drugs.  It being governed by the law of mass action.  It has been realized that occupation of the receptor is essential but not itself sufficient to elicit a response.

RECEPTOR OCCUPATION THEORY  The ability to bind with the receptor designated as Affinity, and the capacity to induce a functional change in the receptor designated as Intrinsic Activity (IA) or Efficacy are independent properties.  A theoretical quantity(S) denoting strength of stimulus imparted to the cell was interposed in the Clark's equation:

RECEPTOR OCCUPATION THEORY TERMSAFFINITYINTINSIC ACTIVITY EXAMPLE AGONISTYES1Adrenaline, Morphine. ANTAGONISTYES0 Atropine, Naloxone. PARTIAL AGONIST YES0 to1pentazocine (on p opioid receptor). INVERSE AGONIST YES0 to -1DMCM (on benzodiazepine receptor).

THE TWO-STATE RECEPTOR MODEL

SOME BASIC EVIDENCES  Many drugs exhibit structural specificity of activity i.e. specific chemical configuration is associated with a particular action.  Chirality of drug molecule. e.g. l-noradrenaline is 10 times more potent than d-noradrenaline.

Drug-Receptor Bonds 1. Covalent Bond - Very strong - Not reversible under biologic conditions - Unusual in therapeutic drugs 2. Ionic bond - Weak, electrostatic attraction between positive and negative forces - Easily made and destroyed 3. Dipole - dipole interaction -A stronger form of dispersion forces formed by the instantaneous dipole formed as a result of electrons being biased towards a particular atom in a molecule (an electronegative atom).

Drug-Receptor Bonds, contd. 4. Hydrophobic interactions - Usually quite weak -Important in the interactions of highly lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with the internal walls of receptor “pockets” 5. Dispersion (Van der Waal) forces -Attractive forces that arise between particles as a result of momentary imbalances in the distribution of electrons in the particles

Criteria in classifying receptors  Pharmacological criteria Based on relative potencies of selective agonists and antagonist. {M & N receptors}  Tissue distribution Relative organ/tissue distribution is the basis.{β 1 & β 2 }  Ligand binding Measurement of specific binding of high affinity radio-labelled ligand to cellular fragment (usually membranes) in vitro.{Multiple 5-HT receptors}

Criteria in classifying receptors  Transducer pathway Specific mechanism through which their activation is linked to the response.{GABA, M cholinergic}  Molecular cloning Receptor protein is cloned out and detailed amino acid sequence as well as 3-dimentional structure is worked out.

G Protein-Linked Receptors

note how activation is reversible the more ligand binding, the greater the cellular response

Ion-Channel Receptors

Tyrosine Kinase Receptors Note steps involved: 1.Ligand Reception 2.Receptor Dimerization 3.Catalysis (Phosphorylization) 4.Subsequent Protein Activation 5.Further Transduction 6.Response

ACKNOWLEDGEMENT  Rang and Dale’s Pharmacology,6 th edition 2007, ELSEVIER publisher.  KD Tripathi, “Essential of Medical Pharmacology",6 th edition, Jaypee publisher.  Basic Receptor Pharmacology by Gunnar Schulte Receptor Biology & Signaling Physiology & Pharmacology, Karolinska Institute,1967; February 2008