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Receptor classification, properties and types. Learning objectives • • • • • Describe the two primary properties of a drug,and how a receptor differs from an inert binding site. Define the following drug properties,agonist,antagonist,partial agonist,affinity,efficacy,potency. Descibe the typical dose response curve for a drug and label the positions on the curve that are used to define drug potency and efficacy. Explain the difference between selectivity and specificity of drug effect,and which is more commonly observed, Explain what is meant by additive,potentiative and synergistic drug effects. Nature of receptors Majority of receptors are protein in nature, a receptor may be: An enzymatic protein: Dihydrofolatereductase e.g. TRIMETHOPRIM Monoamine oxidase e.g. PHENELZINE AND ISOCARBOXAZID Xanthine oxidasee.g ALLOPURINOL Types of receptors • Regulatory – change the activity of cellular enzymes • Enzymes – may be inhibited or activated • Transport – e.g. Na+ /K+ATP’ase • Structural – these form cell parts Examples of receptors Structural protein: Tubulin = colchicin Transport protein: Na – K ATPaseDIGITALIS H – K ATPaseOMEPRAZOLE Ionic channel: Calcium channels = Ca++ blockers Sodium channels = anesthetics Regulatory protein: Mediating the effects of neurotransmitters, hormones and autacoids Nucleic acids (RNA & DNA): For antiviral and anticancer drugs Receptors are situated on surface of cell or inside cell (cytoplasm and nucleus). D+R DR Complex Affinity Affinity – measure of propensity of a drug to bind receptor; the attractiveness of drug and receptor Covalent bonds are stable and essentially irreversible Electrostatic bonds may be strong or weak, but are usually reversible AFFINITY Ability of a drug to bind a receptor is called “AFFINITY” of the drug for receptor. INTRINSIC ACTIVITY Ability of drug to produce pharmacological effect after binding to a receptor is called “INTRINSIC ACTIVITY” Selective binding of a drug to a receptor is specific and implies high degree of complimentarily in their chemical structure. Agonist A drug having high affinity for receptor and has high intrinsic activity is called “AGONIST” OR A drug that initiates a pharmacological action by binding to a receptor thatmimics the action of endogenous compounds is called “AGONIST” Types of Agonist Drugs Two types Full – an agonist with maximal efficacy Partial – an agonist with less then maximal efficacy • • High affinity High intrinsic activity Agonist Agonist PARTIAL AGONIST A drug having same affinity for receptor as an agonist but less intrinsic activity than full agonist is called “PARTIAL AGONIST”. A partial agonist in presence of full agonist acts as antagonist, as it occupies the receptor and does not allow the full agonist to bind with receptor. Agonists and antagonists agonist has affinity plus intrinsic activity antagonist has affinity but no intrinsic activity partial agonist has affinity and less intrinsic activity competitive antagonists can be overcome REVERSE OR INVERSE AGONIST Some drugs produce pharmacological responses by binding to the receptors that are specifically opposite to those of an agonist, such drugs are called “REVERSE OR INVERSE AGONIST.” For example agonist action of benzodiazepines on benzodiazepine receptor in C.N.S produces sedation, muscle relaxation, anxiolysis and controls convulsions. -carolines also bind to these receptors and cause stimulation, anxiety, increased muscle tone and convulsions. Both benzodiazepines and -carolines act as agonist and produce opposing effects, in this example benzodiazepines act as reverse agonist. Antagonist A drug having high affinity for receptor but has poor or no intrinsic activity is called “ANTAGONIST”. OR A drug that bind with receptor but does not initiate action (interfere with binding of agonist) is called “ANTAGONIST”. • High affinity • Antagonist Drug Antagonists interact with the receptor but do NOT change the receptor They have affinity but NO intrinsic activity TYPES Competitive Noncompetitive Competitive Antagonist Competes with agonist for receptor Surmountable with increasing agonist concentration Displaces agonist dose response curve to the right (dextral shift) Reduces the apparent affinity of the agonist Low intrinsic activity Antagonist Reversible Antagonist • • High affinity Low intrinsic activity • High affinity Antagonist • Low intrinsic activity Irreversible Antagonist Irreversible Antagonist Noncompetitive Antagonist Drug binds to receptor and stays bound Irreversible – does not let go of receptor Produces slight dextral shift in the agonist DR curve in the low concentration range This looks like competitive antagonist but, as more and more receptors are bound (and essentially destroyed), the agonist drug becomes incapable of eliciting a maximal effect Receptor properties A drug may act on more than one type of receptors differing both in function and binding characteristics. Drug receptors are dynamic not static. Number of receptors is not fixed but is constantly being changed. When number of receptors is increased it is called “Up Regulation” and when number of receptors is decreased it is called “Down Regulation.” Change in the number of receptors depends upon Disease State Quantity Frequency and duration of the drug used Persistent use of antagonist causes up regulation of receptors and that of agonist causes down regulation of receptors Receptor Regulation Sensitization or Up-regulation 1. Prolonged/continuous use of receptor blocker 2. Inhibition of synthesis or release of hormone/neurotransmitter Denervation Desensitization or Down-regulation 1. Prolonged/continuous use of agonist 2. Inhibition of degradation or uptake of agonist Desensitization Agonists tend to desensitize receptors Homologous (decreased receptor number) Heterologous (decreased signal transduction) Antagonists tend to up regulate receptors Signaling Mechanisms Binding of an agonist drug to its receptor activates an effector or signaling mechanism. Several different types of drug responsive signaling mechanisms are known. Intracellular receptors These include receptors for steroids, thyroxine, gonadal steroids and vitamin D. • Binding of drugs or hormones to such receptors cause dimerization of hormone receptor complex. • Such complexes translocate to the nucleus, where they interact with response elements in spacer DNA. • This leads to changes in gene expression. • Pharmacologic responses elicited via modification of gene expression are slower in onset but longer in duration. • Membrane receptors directly coupled to ion channels • Drugs bind to receptors on membrane and regulate flow of ions through them. • Do not require secondary messengers i.e. directly coupled to ion channels. • Examples • Acetylcholine in neuromuscular junction coupled to Na ion channels • GABA receptors coupled to Cl ion channels • • Receptors linked via G- proteins • Many receptors are coupled via GTP binding proteins (G-proteins) to adenylyl cyclase, the enzyme that converts ATP to cAMP, a second messenger that promotes protein phosphorylation by activating protein kinase A. • • These receptors are typically serpentine with 7 transmembrane spanning domains • Gs Proteins • Binding of agonists to receptors linked to Gs proteins increases cAMP production. • Examples include catecholamine (beta receptors), glucagon receptors, histamine (H2) etc. • Gi Proteins • Binding of agonists to receptors linked to Gi proteins decreases cAMP production • Examples include catecholamine (alpha 2), Ach (M2) etc. • Receptors linked via G- proteins • Gq Proteins • Gq system activates Phospholipase C. • • Cyclic GMP and Nitric Oxide signaling • cGMP is a second messenger in vascular smooth muscle that facilitates dephosphorylation of myosin light chains, preventing their interaction with actin and thus causing vasodilation. • NO is synthesized in endothelial cells and diffuses into smooth muscles. • NO activates guanylyl cyclase, thus increasing cGMP in smooth muscles. • Receptors that function as transmembrane enzymes • Classic example is insulin • • Receptors for insulin are membrane spanning molecules with recognition sites for insulin and a cytoplasmic domain that functions as a tyrosine kinase. • • Receptors for Cytokines • These receptors are membrane spanning and on activation can activate a distinctive set of cytoplasmic tyrosine kinases (janus kinase JAKs) • • JAKs phosphorylate signal transducers and activators of transcription (STAT) moecules. • • Examples include receptors for erythropoietin, somatotropin and interferons Signaling Mechanisms & G- Protein coupled receptors Signaling Mechanisms Binding of an agonist drug to its receptor activates an effector or signaling mechanism. Several different types of drug responsive signaling mechanisms are known. Intracellular receptors These include receptors for steroids, thyroxine, gonadal steroids and vitamin D. Binding of drugs or hormones to such receptors cause dimerization of hormone receptor complex. Such complexes translocate to the nucleus, where they interact with response elements in spacer DNA. . This leads to changes in gene expression Pharmacologic responses elicited via modification of gene expression are slower in onset but longer in duration. Membrane receptors directly coupled to ion channels Many drugs act by mimicking or antazonizing the actions of endogenous ligands that regulate flow of ions through excitable membranes via their activation of receptors that are directly coupled to ion channels Do not require secondary messengers i.e. directly coupled to ion channels. Example Acetylcholine receptors in neuromuscular junction, ANS ganglia and CNS are coupled to Na ion channels. Example GABA receptor in the CNS, which is coupled to a chloride ion channel, can be modulated by anticonvulsants, benzodiazepines and barbiturates. Receptors linked via G- proteins Many receptors are coupled via GTP binding proteins (G-proteins) to adenylyl cyclase, the enzyme that converts ATP to cAMP, a second messenger that promotes protein phosphorylation by activating protein kinase A. These receptors are typically serpentine with 7 transmembrane spanning domains. Protein kinase A serves to phosphorylate a set of tissue specific substrate enzymes or transcription factors (CREB), thereby affecting their activity. Gs Proteins Binding of agonists to receptors linked to Gs proteins increases cAMP production. Examples include catecholamine (beta receptors), glucagon receptors, histamine (H2) etc. Gi Proteins Binding of agonists to receptors linked to Gi proteins decreases cAMP production Examples include catecholamine (alpha 2), Ach (M2) etc. Gq Proteins Gq system activates Phospholipase C. Activation of Phospholipase C releases the second messengers inositol triphosphate (IP3) and diacylglycerol from the membrane phospholipid phosphatidylinositol biphosphate (PIP2) The IP3 induces release of Ca+2 from sarcoplasmic reticulum which together with DAG activates protein kinase C. Examples: norepinephrine (alpha 1), angiotensin II and several serotonin subtypes. Cyclic adenosine monophosphate (cAMP, cyclic AMP • • 3'-5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is derived from adenosine triphosphate (ATP) and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent . pathway Cyclic GMP and Nitric Oxide signaling cGMP is a second messenger in vascular smooth muscle that facilitates dephosphorylation of myosin light chains, preventing their interaction with actin and thus causing vasodilation. NO is synthesized in endothelial cells and diffuses into smooth muscles. NO activates guanylyl cyclase, thus increasing cGMP in smooth muscles. Receptors that function as enzymes or transporters There are multiple examples of drug action that depend on enzyme inhibition, including inhibitors of acetylcholinesterase, ACE, carbonic anhydrase etc. Examples of drug action on transporter systems include inhibitors of reuptake of several neurotransmitters like dopamine, norepinephrine, GABA etc. Receptors that function as transmembrane enzymes Classic example is insulin Receptors for insulin are membrane spanning molecules with recognition sites for insulin and a cytoplasmic domain that functions as a tyrosine kinase. Receptors for Cytokines These receptors are membrane spanning and on activation can activate a distinctive set of cytoplasmic tyrosine kinases (janus kinase JAKs) JAKs phosphorylate signal transducers and activators of transcription (STAT) moecules. Examples include receptors for erythropoietin, somatotropin and interferons