Medicinal Chemistry/ CHEM 458/658 Chapter 8- Receptors and Messengers

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1 Medicinal Chemistry/ CHEM 458/658 Chapter 8- Receptors and Messengers Bela Torok Department of Chemistry University of Massachusetts Boston Boston, MA 1

2 Introduction Receptor specific areas of proteins - embedded in the cell membrane - nucleus ligand (endogenous/exogenous) and binding domain, biological response secondary messengers, possibility of intervention signal transduction 2

3 Introduction secondary messengers, possibility of intervention agonists and antagonists (several groups of xenobiotics, not just drugs) 3

4 The Chemistry of the Ligand-Receptor Binding Full spectrum of chemical bonding ligand to receptor diffusion or transport proteins 4

5 The Chemistry of the Ligand-Receptor Binding Full spectrum of chemical bonding - charge-transfer complexes - hydrophobic bonding and London dispersion forces 5

6 Structure and Classification of Receptors Family 1 - endogenous ligand: fast neurotransmitters - nachr, GABA A or glutamate receptors) - general structure Four/five subunits with total of membrane-spanning domains. 6

7 Structure and Classification of Receptors Family 2 - endogenous ligand: hormones and slow transmitters - machr and noradrenergic receptors ( it is coupled to the effector system by G-protein) - general structure 7

8 Structure and Classification of Receptors Family 3 - endogenous ligand: insulin and growth factors - insulin receptors ( it is linked to tyrosine kinase) - general structure 8

9 Structure and Classification of Receptors Family 4 - endogenous ligand: steroid hormones, thyroid hormones, vitamins (D), retinoic acid - antidiuretic hormone (ADH) or vasopressing receptors - general structure 9

10 Structure and Classification of Receptors Further classification - e.g. machr or nachr, even further m 1 AChR m 5 AChR - α or β adrenoreceptors 10

11 General Mode of Operation Ligands activate or deactivate (inhibit) primary messengers - primary messengers: hormones, neurotransmitters other endogenous substances, or xenobiotics (drugs, bacteria, virus) Hormones: autocoids 11

12 General Mode of Operation Ligands activate or deactivate (inhibit) primary messengers - primary messengers: hormones, neurotransmitters other endogenous substances, or xenobiotics (drugs, bacteria, virus) Neurotransmitters: 12

13 Mode of action: Superfamily 1/2 General Mode of Operation 13

14 Superfamily 1 ion channel control e.g. nachr General Mode of Operation 14

15 General Mode of Operation Superfamily 2 most receptors have one polypeptide chain 15

16 General Mode of Operation Superfamily 2 role of G proteins 16

17 General Mode of Operation Superfamily 2 role of G proteins 17

18 General Mode of Operation Superfamily 2 role of G proteins 18

19 Superfamily 3 General Mode of Operation 19

20 Superfamily 4 General Mode of Operation 20

21 Ligand-Response Relationships L R binding loss of energy (affinity) L R L + R L + R L R K D = L R L R K a = L R L R pd 2 =-logk D =-logec 50 21

22 Ligand-Response Relationships Experimental Determination of L-R curves 22

23 Ligand-Response Relationships Experimental Determination of L-R curves 23

24 Ligand-Response Relationships Agonist Concentration-Response Relationships 24

25 Ligand-Response Relationships Antagonist Concentration-Response Relationships 25

26 Ligand-Response Relationships Antagonist Concentration-Response Relationships 26

27 Ligand-Response Relationships Antagonist Concentration-Response Relationships 27

28 Ligand-Response Relationships Partial Agonists act both ways - multiple pharmacophores that act differently - reasonable but not perfect fits 28

29 Desensitization Ligand-Response Relationships 29

30 Ligand-Receptor Theories Clark s occupancy theory E Emax = [DR] [R T ] = [D] K D +[D] K D = EC 50 30

31 Clark s occupancy theory Ligand-Receptor Theories new developments: - many D-R complex formations are not reversible - the R sites are not always independent - not every D-R formation is bimolecular - max response maybe obtained before every R is occupied - the response is not linear to the proportions of receptors occupied Ariens and Stephenson (1950s) intrinsic activity/efficacy E = max ofadrug E max ofthemostactiveagonistinthesamestructuralseries E Emax = [DR] [R T ] = [D] K D +[D] 31

32 Ligand-Receptor Theories The Rate Theory (Paton, 1961) - stimulation only when the ligand first occupies the receptor - second conformational change more stable complex - when ligand leaves further stimulus can occur - type of activity is independent of the number of receptors, it depends on the rate of binding/release correlation : poor The Two-State Model - receptors exist in an active/inactive state (relaxed/r, tensed/t) - equilibrium between the two states 32

33 Drug Action and Design Agonists 33

34 Drug Action and Design Agonists 24X activity 400X activity 34

35 Drug Action and Design Antagonists 35

36 Drug Action and Design Case study 1 CNS drugs citalopram antagonist antidepressant 36

37 Drug Action and Design Case study 1 CNS drugs citalopram antagonist antidepressant 37

38 Case study 1 CNS drugs citalopram Drug Action and Design 38

39 Drug Action and Design Case study 2 β blockers (β adrenoreceptor antagonists in the heart) 39

40 Drug Action and Design Case study 2 β blockers (β adrenoreceptor antagonists in the heart) vasodilation decreases blood glucose level pupil constriction causes impotence decreases heart rate decreases blood pressure increase in gut secretions and motility bronchocontsriction decreases blood glucose 40

41 Drug Action and Design Case study 2 selective β blockers (β adrenoreceptor antagonists in the heart) 41