Drug receptor interactions and types of receptor

Receptor types, mechanism, receptor pharmacology, drug receptor interactions, theories of receptor pharmacology, spare receptors and new concepts like biased agonism

1. DRUG RECEPTOR INTERACTIONS Dr. S iddhartha Dutta Mamc , New D elhi

2. CONTENTS Introduction Targets for drug binding Types of receptors Determinants of drug activity Receptor theories Drug receptor interactions Desensitisation and tachyphylaxis Conclusion

3. history 1878 – John Langley 1905 - Receptive substance on surface of skeletal muscle mediate drug action. Different in different species Paul Ehrlich designated 'receptor‘ to be anchoring group of the protoplasmic molecule for the administered compound “ Corpora non agunt nisi fiata ”

4. 1948 - Ahlquist showed the differential action of adrenaline & demonstrated its effects on two distinct receptor populations & the theory of receptor-mediated drug interactions gained acceptance 1970s - Pharmacology entered a new phase following the development of receptor- labelling techniques which made it possible to extract and purify the receptor material .

5. TARGETS FOR DRUG BINDING

6. Drug is any substance or product that is used for diagnosis , prevention , treatment/cure of a disease or is intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient.

7. HOW DRUGS ACT Enzyme Inhibition: Modifying normal biochemical reactions. Reversible or non reversible/ Competitive or non-competitive Antimetabolites may be used which mimic natural metabolites Gene functions may be suppressed. Drug-Receptor Interaction:: Physical and/or chemical interactions Specific drug receptor sites known to be located on the membrane Some receptor sites have been identified with specific parts of proteins and nucleic acids Non-specific Interactions: Act exclusively by physical means outside of cells Drugs also act outside of cell membranes by chemical interactions

8. Cellular macromolecule, or an assembly of macromolecules, mainly protein in nature present on the surface of the cell membrane or inside the cell , concerned directly and specifically in chemical signaling between and within the cells

9. TYPES OF RECEPTORS Ligand Gated Ion Channels G-Protein Coupled receptors Enzyme Linked receptors Nuclear receptors

10. LIGAND GATED ION CHANNELS Ionotropic Receptors Typically receptors on which fast neurotransmitters act Timescale: Milliseconds Localization: Membrane Effector: Ion Channel Coupling: Direct Gating mechanism : conformational change occurs in extracellular part of the receptor Examples : Nicotinic Ach Receptor, GABA-A Receptor, Glutamate Receptor , Glycine receptor, 5–HT3, AMPA & kinate receptors

11. VOLTAGE OPERATED CHANNELS These channels open when the cell membrane is depolarised . They underlie the mechanism of membrane excitability Activation induced by membrane depolarisation is short lasting, even if the depolarisation is maintained The most important channels in this group are selective sodium, potassium or calcium channels

12. G – PROTEIN – COUPLED RECEPTORS Largest family Metabotropic or 7– Transmembrane / Heptahelical ( α- helices) receptors E xtracellular N-terminal domain and intracellular C-terminal domain 3rd cytoplasmic loop couples to the G- Protein Timescale : Seconds Location : Membrane Effector : Channel or Enzyme Coupling : G- Protein Examples : adrenoceptors , Muscarinic Ach, histamine, serotonin, opioid, cannabinoid, amine, peptide, prostanoid receptors

13. Varieties of G-protein G-protein Receptor for Signaling pathway/ Effector Gs ß adrenegic, H,5HT,Glucagon AC— cAMP Gi 1,2,3 α 2 adrenergic, Ach, AC— cAMP, Open K + Gq Ach Phospholipase-C, IP 3 ’ cytoplasmic Ca +2 Go Neurotransmitters in brain Not yet clear

14. Targets for G-Proteins Adenylate cyclase

15. Phospholipase C/IP3/DAG

16. Ion Channels like K⁺ and Ca ⁺⁺ channels are controlled by direct interaction between the βγ- subunit of G and the channel Phospholipase A2(formation of arachidonic acid and eicosanoids) Rho A/Rho kinase , a system that controls the activity of many signaling pathways controlling cell growth and proliferation, smooth muscle contraction, etc. Mitogen-activated protein kinase ( MAP kinas e), activated by cytokines and growth factors acting on kinase-linked receptors and by GPCR ligands. Controls processes involved in cell division, apoptosis and tissue regeneration

17. KINASE LINKED AND RELATED RECEPTORS Large, heterogenous group responding mainly to protein mediators. Timescale : Hours Location : Membrane Effector : Protein Kinases Coupling : Direct Examples : Insulin, Growth Factors, Cytokine, ANF receptors

18. NUCLEAR RECEPTORS Two main categories: Present in the cytoplasm , form homodimers and migrate to the nucleus. Their ligands are mainly endocrine in nature (e.g. steroid hormones) constitutively present in the nucleus and form heterodimers with the retinoid X receptor . Their ligands are usually lipids (e.g. fatty acids). A third subgroup transduce mainly endocrine signals but function as heterodimers with retinoid X receptor (e.g . thyroid hormone). ligand-receptor complexes initiate changes in gene transcription by binding to hormone response elements in gene promoters and recruiting co-activator or co-repressor factors

19. Drug specificity Proteins that function as drug targets generally show a high degree of ligand specificity No drug acts with complete specificity Lower the potency of a drug and the higher chances of unwanted side effects, of which no drug is free

20. Drug receptor interactions LIGAND : A ny molecule which attaches selectively to particular receptor AFFINITY: C apability of drug to bind to the receptor and form receptor complex INTRINSIC ACTIVITY : A bility of the drug to trigger the pharmacological response after forming complex

21. Determinants of Drug Activity Efficacy: The ‘strength’ of the agonist–receptor complex in evoking a response of the tissue Potency: Amount of drug needed to produce an effect.

22. Receptor theories

23. Occupation  theory, clark’s (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 . D + R  DR  RESPONSE Intensity of pharmacological effect is directly proportional to number of receptors occupied      The response ceases when this complex dissociates Maximal  response occurs when all the receptors  are  occupied at equilibrium Limitations ??

24. THE INDUCED-FIT THEORY, daniel koshland (1958) States that the morphology of the binding site is not necessarily complementary to the preferred conformation of the ligand Binding produces a mutual plastic molding of both the ligand and 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 Agonist induces conformational change – response Antagonist does not induce conformational change – no response Partial agonist induces partial conformational change - partial response

25. Paton’s Rate theory (1961) The response is proportional to the rate of drug-Receptor complex formation E ffect is produced by the drug molecules based on the rates of association and dissociation of drugs to and from the receptors Antagonists act much more slowly than agonists do and hence the rate of dissociation is inversely proportional to the potencies of antagonists while is directly proportional to the agonists Type of effect is independent of number of receptors rather rate of binding and release from the receptor .

26. THE TWO-STATE (MULTISTATE) RECEPTOR MODEL D eveloped on the basis of the kinetics of competitive and allosteric inhibition It postulates that a receptor, regardless of the presence or absence of a ligand , exists in two distinct states: the R(active) and R * (inactive) states R and R* are in equilibrium (equilibrium constant L), which defines the basal activity of the receptor O ccupied receptor can switch from its ‘resting’ (R) state to an activated (R*) state, R* being favored by binding of an agonist but not an antagonist molecule

27. Added drug encounters an equilibrium mixture of R and R * If it has a higher affinity for R* than for R, the drug will cause a shift of the equilibrium towards R* (i.e. it will promote activation and be classed as an agonist ) If its preference for R* is very large , nearly all the occupied receptors will adopt the R* conformation and the drug will be a full agonist (positive efficacy ) S hows only a modest degree of selectivity for R * , a smaller proportion of occupied receptors will adopt the R* conformation(partial agonist Shows no preference , the prevailing R:R* equilibrium will not be disturbed and the drug will be a neutral antagonist(zero efficacy) Shows selectivity for R it will shift the equilibrium towards R and be an inverse agonist (negative efficacy)

28. AGONIST A drug that binds to physiological receptor and mimic the regulatory effects of endogenous substance. It has high affinity and high intrinsic activity

29. Types of agonism Summation :- Two drugs eliciting same response , but with different mechanism and their combined effect is equal to their summation. Aspirin Codiene PG Opiods receptor Analgesic+ Analgesic+ ++

30. Additive: combined effect of two drugs acting by same mechanism Aspirin NSAIDS PG PG Analgesic+ Analgesic+ + +

31. Synergism (Supra additive):- The combined effect of two drug effect is higher than either individual effect. 1.Sulfamethaxazole+ Trimethoprim 2. Levodopa + Carbidopa .

32. PARTIAL AGONIST F ull affinity + low intrinsic activity Partly as effective as agonist Greater affinity for RA than RI Cannot produce a full biological response at any concentration ex: Pentazocine

33. INVERSE AGONIST: Full affinity & intrinsic activity<0(0 to-1 ) Inverse agonists bind with the constitutively active receptors, stabilize them, and thus reduce the activity (negative intrinsic activity). Eg . Beta carbolines on BZD receptor Chlorpheneramine on H1 , Risperidone /clozapine/chlorpromazine on 5-HT2a Ziprasidone /olanzapine on 5-HT2c

34. antagonist A drug is said to be an antagonist when it binds to a receptor and prevents (blocks or inhibits) a natural compound or a drug to have an effect on the receptor . An antagonist has no activity . Types of Antagonism Chemical antagonism Physiological /Functional antagonism Pharmacokinetic antagonism Pharmacological antagonism Competitive ( Reversible/irreversible) Non competitive (Irreversible)

35. PHARMACOKINETIC ANTAGONISM Antagonist effectively reduces the concentration of the active drug at its site of action Either by increased metabolic degradation, decreased absorption or increased excretion A - Calcium & tetracycline, Cholestyramine & warfarin/digoxin D- P henylbutazone & warfarin M - ↑ Phenobarbital/rifampicin & warfarin, rifampicin & OCP ↓ ciprofloxacin/chloramphenicol/erythromycin & theophylline E- ↓ P robencid /aspirin/sulfonamides/thiazides/indomethacin & penicillin/ zidovudine , NSAIDS & methotrexate/ furosemide ↑ excretion of weak acid/ bases during poisioning

36. Pharmacological antagonism Competitive antagonism- Reversible - Irreversible Reversible antagonism Antagonists that bind reversibly to the same receptor site as that of an agonist Surmountable Shift of the agonist log concentration–effect curve to the right, without change of slope or maximum effect Linear relationship between agonist dose ratio and antagonist concentration

37. Shift is expressed as a dose ratio , r , ( the ratio by which the agonist concentration has to be increased in the presence of t he antagonist in order to restore a given level of response ) Agonist reduces the rate of association of the antagonist molecules Consequently , the rate of dissociation temporarily exceeds that of association, and the overall antagonist occupancy falls.

38. Irreversible Antagonism It occurs when the antagonist dissociates very slow or not at all from the receptors results no change when the agonist applied. Antagonist effect cannot be overcome even after increasing the concentration of agonist Occurs with drugs that possess reactive groups that form covalent bonds with the receptor Aspirin, omeprazole and MAO inhibitors

39. SPARE RECEPTORS Receptors are said to be spare when, the maximal response can be elicited by an agonist at a concentration that does not result in 100% occupancy of available receptors Agonist has to bind only a portion of receptors for full effect-increase sensitivity of the system M any full agonists are capable of eliciting maximal responses at very low occupancies, often less than 1% Spare receptors, or a receptor reserve denotes that the pool is larger than the number needed to evoke a full response For a biological response economy of hormone or transmitter secretion is thus achieved at the expense of providing more receptors

40. DESENSITISATION & TACHYPHYLAXIS TACHYPHYLAXIS The effect of a drug gradually diminishes when it is given continuously or repeatedly, which often develops in the course of minutes Tolerance - Gradual decrease in responsiveness to a drug, taking days or weeks to develop . Refractoriness is used to indicate loss of therapeutic efficacy Drug resistance is used to indicate loss of effectiveness of antimicrobial or anti tumor drugs

41. Mechanism of desensitisation C hange in receptors- Ion channels Translocation of receptors- beta adrenoreceptor Exhaustion of mediators-amphetamines Increased metabolic degradation-alcohol/nitrates Physiological adaptation-thiazide

42. Biased agonism Biased agonism , the ability of a receptor to differentially activate downstream signaling pathways depending on binding of a “biased” agonist compared to a “balanced” agonist The ability of some ligands to selectively activate some signaling pathways while blocking others Peptides PACAP 1-27 and PACAP 1-38 activate PACAP (pituitary cyclase -activating polypeptide type 1) receptors to elevate cyclic AMP and increase production of IP3 The receptor is not the minimal unit of control of agonism , it is the agonist-receptor complex that controls the ultimate signaling event N ature of the receptor-active state and the interaction of the activated receptor with the multiple cytosolic signaling proteins

43. Molecular dynamics predicts that when proteins such as receptors change conformation , different regions of the receptor change independently (i.e., the protein does not form uniform global conformation) S ignaling protein s interact with different regions of the receptor Unique receptor conformations stabilized by agonists most likely will result in differential (biased) activation of cell signaling pathways A ctivation of a receptor that interacts with multiple signaling components in a cell most likely will never produce equal activation of all pathways Functionally selective agonists are defined as having a signaling bias different from that of the natural agonist

44. conclusion

45. THANK YOU