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Radioligands for GABA and AcCh receptors

Radioligands for GABA and AcCh receptors. GABA. ionotropic receptors: GABA A receptors metabotropic receptors: GABA B receptors. AcCh. ionotropic receptors: nicotinic receptors metabotropic receptors: muscarinic receptors.

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Radioligands for GABA and AcCh receptors

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  1. Radioligands for GABA and AcCh receptors GABA • ionotropic receptors: GABAA receptors • metabotropic receptors: GABAB receptors AcCh • ionotropic receptors: nicotinic receptors • metabotropic receptors: muscarinic receptors

  2. Ion-transport mechanisms underlying GABAA receptor-mediated responses in immature (left) and mature (right) neurons. NKCC1 mediates Cl– uptake in immature hippocampal and cortical neurons. In mature CNS neurons, KCC2 is the principal K-Cl cotransporter. Cl– transport is fuelled by the Na+ and K+ gradients generated by the Na-K ATPase. Intracellular concentration of Cl– is high in immature neurons (indicated by the shade of blue). Blaesse et al. (2009) Cation-Chloride Cotransporters and Neuronal Function. Neuron 61, 820-838.

  3. Radioligands for GABA and AcCh receptors GABA Muscimol (an isoxazole) • ionotropic receptors: GABAA receptors • metabotropic receptors: GABAB receptors AcCh • ionotropic receptors: nicotinic receptors • metabotropic receptors: muscarinic receptors Bicuculline, Bicuculline methochloride

  4. Radioligands for GABA and AcCh receptors  University Colorado

  5. Radioligands for GABA and AcCh receptors t-Butyl bicyclo phosphorothionate (TBPS) GABA • ionotropic receptors: GABAA receptors • metabotropic receptors: GABAB receptors AcCh Flumazenil Flunitrazepam • ionotropic receptors: nicotinic receptors • metabotropic receptors: muscarinic receptors Allopregnanolone (a steroid)

  6. Radioligands for GABA and AcCh receptors GABA • ionotropic receptors: GABAA receptors b-carboline-3-carboxylic acid, ethyl ester • metabotropic receptors: GABAB receptors AcCh Pena, Medina, Novas, Paladini, De Robertis (1986) Isolation and identification in bovine cerebral cortex of n-butyl b-carboline-3-carboxylate, a potent benzodiazepine binding inhibitor. PNAS 83:4952 • ionotropic receptors: nicotinic receptors • metabotropic receptors: muscarinic receptors

  7. Radioligands for GABA and AcCh receptors GABA • ionotropic receptors: GABAA receptors (R)-Baclofen • metabotropic receptors: GABAB receptors AcCh • ionotropic receptors: nicotinic receptors • metabotropic receptors: muscarinic receptors SKF 97541 CGP 54 626 (phosphinic acids)

  8. Radioligands for GABA and AcCh receptors Acetylcholine Carbamylcholine (Carbachol) GABA • ionotropic receptors: GABAA receptors • metabotropic receptors: GABAB receptors N-Methylcarbamylcholine Nicotine AcCh • ionotropic receptors: nicotinic receptors Epibatidine • metabotropic receptors: muscarinic receptors 5-I-A85380

  9. Radioligands for GABA and AcCh receptors GABA • ionotropic receptors: GABAA receptors • metabotropic receptors: GABAB receptors Structures of major alkaloids present in tobacco. (S)-Nicotine is the predominant enantiomer in tobacco. The other alkaloids exist in tobacco as not very precisely defined mixtures of enantiomers (Pogocki et al. 2007, Eur. J. Pharmacol. 563: 18). Nicotine AcCh • ionotropic receptors: nicotinic receptors Epibatidine • metabotropic receptors: muscarinic receptors 5-I-A85380

  10. Radioligands for GABA and AcCh receptors GABA • ionotropic receptors: GABAA receptors • metabotropic receptors: GABAB receptors Epipedobates tricolor (John W Daly 1933-2008) Nicotine AcCh • ionotropic receptors: nicotinic receptors Epibatidine • metabotropic receptors: muscarinic receptors 5-I-A85380

  11. Radioligands for GABA and AcCh receptors Oxotremorine (agonists) Oxotremorine-M GABA • ionotropic receptors: GABAA receptors • metabotropic receptors: GABAB receptors QNB (Quinuclidinyl-benzilate) AcCh • ionotropic receptors: nicotinic receptors • metabotropic receptors: muscarinic receptors Pirenzepine AF-DX 384 (M1) (M2)

  12. Association & Dissociation BL(t) = BL. (1 - e-nt) BL(t) = BL- BL. e-nt BL- BL(t) = e-nt BL n (greek letter n) ... apparent association rate constant

  13. Association & Dissociation BL(t) = BL. (1 - e-nt) BL(t) = BL- BL. e-nt BL- BL(t) = e-nt BL BL ln = nt BL- BL(t) n (greek letter n) ... apparent association rate constant

  14. Association & Dissociation BL(t) = BLo. e-bt BL(t) = e-bt BLo b ... dissociation rate constant

  15. Association & Dissociation BL(t) = BLo. e-bt BL(t) = e-bt BLo BL(t) ln = -bt BLo b ... dissociation rate constant

  16. Association & Dissociation Only if the ligand binds covalently (irreversible binding), all bindings sites (BM) are occupied.

  17. Association & Dissociation If presented as % of finally achieved occupancy (B∞), the reversible process is recognized as faster.

  18. Association & Dissociation What is the true association rate constant? a B + L BL b association rate: a . [B] . [L] dissociation rate: b . [BL] equilibrium: a . [B] . [L] = b . [BL] [B] . [L] KD = = b / a [BL]

  19. ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention ! a Association & Dissociation B + L BL b How is the true association rate constant related to the apparent association rate constant? d[BL] = a . [B] . [L] – b . [BL] dt ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention !

  20. ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention ! a Association & Dissociation B + L BL b How is the true association rate constant related to the apparent association rate constant? d[BL] = a .[B]. [L] – b . [BL] dt [B] = BM – [BL] ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention !

  21. ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention ! a Association & Dissociation B + L BL b How is the true association rate constant related to the apparent association rate constant? d[BL] = a . [B] . [L] – b . [BL] dt [B] = BM – [BL] [L] at equilibrium [BL]∞ = BM. [L] + KD replace by b/a ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention !

  22. ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention ! a Association & Dissociation B + L BL b How is the true association rate constant related to the apparent association rate constant? d[BL] = a . [B] . [L] – b . [BL] dt [B] = BM – [BL] [L] [L] + b/a at equilibrium [BL]∞ = BM. BM = [BL]∞ ⋅ [L] + KD [L] ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention !

  23. ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention ! a Association & Dissociation B + L BL b How is the true association rate constant related to the apparent association rate constant? d[BL] = a . [B] . [L] – b . [BL] dt [B] = BM – [BL] [L] [L] + b/a at equilibrium [BL]∞ = BM. BM = [BL]∞ ⋅ [L] + KD [L] [L] + b/a [B] = [BL]∞ ⋅ – [BL] [L] ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention !

  24. ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention ! a Association & Dissociation B + L BL b How is the true association rate constant related to the apparent association rate constant? d[BL] = a . [B] . [L] – b . [BL] dt [B] = BM – [BL] [L] [L] + b/a at equilibrium [BL]∞ = BM. BM = [BL]∞ ⋅ [L] + KD [L] [L] + b/a [B] = [BL]∞ ⋅ – [BL] [L] d[BL] = a . [BL]∞. ([L] + b/a) – a . [L] . [BL] – b . [BL] dt ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention !

  25. ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention ! a Association & Dissociation B + L BL b How is the true association rate constant related to the apparent association rate constant? d[BL] = a . [B] . [L] – b . [BL] dt [B] = BM – [BL] [L] [L] + b/a at equilibrium [BL]∞ = BM. BM = [BL]∞ ⋅ [L] + KD [L] [L] + b/a [B] = [BL]∞ ⋅ – [BL] [L] d[BL] = a . [BL]∞. ([L] + b/a) – a . [L] . [BL] – b . [BL] dt = ([BL]∞ – [BL]) . (a . [L] + b) ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention !

  26. ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention ! a Association & Dissociation B + L BL b How is the true association rate constant related to the apparent association rate constant? d[BL] = (a . [L] + b) . dt [BL]∞ - [BL] d[BL] = ([BL]∞ – [BL]) . (a . [L] + b) dt ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention !

  27. ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention ! a Association & Dissociation B + L BL b How is the true association rate constant related to the apparent association rate constant? d[BL] = (a . [L] + b) . dt [BL]∞ - [BL] [BL]∞ ln = (a . [L] + b) . t = n. t [BL]∞ - [BL] ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention !

  28. a Association & Dissociation B + L BL b How is the true association rate constant related to the apparent association rate constant? BL(t) = BL. (1 - e-nt) BL(t) = BL- BL. e-nt BL- BL(t) = e-nt BL BL ln = nt BL- BL(t) n (greek letter n) ... apparent association rate constant

  29. ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention ! a Association & Dissociation B + L BL b How is the true association rate constant related to the apparent association rate constant? d[BL] = (a . [L] + b) . dt [BL]∞ - [BL] [BL]∞ ln = (a . [L] + b) . t = n. t [BL]∞ - [BL] a . [L] + b = n true apparent association rate constant ! attention ℮ ∫ ∑mathematics∂ ∞ √ % attention !

  30. a Association & Dissociation B + L BL b n = a . [L] + b dissociation rate constant a . [L] + b = n true apparent association rate constant

  31. Radioligands for NA, DA and 5HT receptors Noradrenaline a-receptors b-receptors Dopamine D1,D2,D3,D4,D5 Serotonin (5-Hydroxytryptamine) ionotropic: 5HT3 metabotrop: 5HT1,5HT2, 5HT4, 5HT6, 5HT7 Ligands for uptake carriers

  32. Radioligands for NA, DA and 5HT receptors Noradrenaline a-receptors b-receptors Prazosine (a1) Dopamine D1,D2,D3,D4,D5 Idazoxane (a2 antagonists) RX 821002 Serotonin (5-Hydroxytryptamine) Clonidine (a2 agonist) ionotropic: 5HT3 metabotrop: 5HT1,5HT2, 5HT4, 5HT6, 5HT7 Ligands for uptake carriers

  33. Radioligands for NA, DA and 5HT receptors Radioligands for NA, DA and 5HT receptors CGP 26505 (antagonist, b1) Noradrenaline Noradrenaline Dihydroalprenolol (antagonist) a-receptors b-receptors Dopamine D1,D2,D3,D4,D5 Serotonin (5-Hydroxytryptamine) ionotropic: 5HT3 metabotrop: 5HT1,5HT2, 5HT4, 5HT6, 5HT7 ICI-118.551 (antagonist, b2) Ligands for uptake carriers

  34. Radioligands for NA, DA and 5HT receptors Noradrenaline a-receptors b-receptors Dopamine Haloperidol Spiroperidol D1,D2,D3,D4,D5 Serotonin (5-Hydroxytryptamine) ionotropic: 5HT3 metabotrop: 5HT1,5HT2, 5HT4, 5HT6, 5HT7 Ligands for uptake carriers Sulpiride

  35. Radioligands for NA, DA and 5HT receptors Noradrenaline a-receptors b-receptors Dopamine Haloperidol D1,D2,D3,D4,D5 Serotonin (5-Hydroxytryptamine) Mavlyutov et al (2010) The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons. An anatomical and behavioral study. Neurosci 167: 247 ionotropic: 5HT3 metabotrop: 5HT1,5HT2, 5HT4, 5HT6, 5HT7 Ligands for uptake carriers

  36. Radioligands for NA, DA and 5HT receptors Noradrenaline a-receptors b-receptors SCH 23390 (D1) Dopamine D1,D2,D3,D4,D5 Serotonin (5-Hydroxytryptamine) ionotropic: 5HT3 metabotrop: 5HT1,5HT2, 5HT4, 5HT6, 5HT7 Ligands for uptake carriers

  37. Radioligands for NA, DA and 5HT receptors Noradrenaline a-receptors b-receptors SCH 23390 (D1) 7-OH-DPAT (D3) Dopamine D1,D2,D3,D4,D5 Serotonin (5-Hydroxytryptamine) ionotropic: 5HT3 metabotrop: 5HT1,5HT2, 5HT4, 5HT6, 5HT7 Ligands for uptake carriers

  38. Radioligands for NA, DA and 5HT receptors Noradrenaline a-receptors b-receptors SCH 23390 (D1) 7-OH-DPAT (D3) Dopamine D1,D2,D3,D4,D5 Clozapine (D4) Serotonin (5-Hydroxytryptamine) ionotropic: 5HT3 metabotrop: 5HT1,5HT2, 5HT4, 5HT6, 5HT7 L-750.667 (D4) Ligands for uptake carriers

  39. Radioligands for NA, DA and 5HT receptors Noradrenaline a-receptors b-receptors Flunitrazepam (benzodiazepine) Dopamine D1,D2,D3,D4,D5 Clozapine (dibenzodiazepine) Serotonin (5-Hydroxytryptamine) ionotropic: 5HT3 metabotrop: 5HT1,5HT2, 5HT4, 5HT6, 5HT7 Ligands for uptake carriers

  40. Radioligands for NA, DA and 5HT receptors Noradrenaline a-receptors b-receptors SCH 23390 (D1) 7-OH-DPAT (D3) Dopamine D1,D2,D3,D4,D5 Olanzapine Serotonin (5-Hydroxytryptamine) ionotropic: 5HT3 metabotrop: 5HT1,5HT2, 5HT4, 5HT6, 5HT7 L-750.667 (D4) Ligands for uptake carriers

  41. Radioligands for NA, DA and 5HT receptors Noradrenaline a-receptors b-receptors Dopamine D1,D2,D3,D4,D5 http://criticalpsychiatry.blogspot.com Serotonin (5-Hydroxytryptamine) ionotropic: 5HT3 metabotrop: 5HT1,5HT2, 5HT4, 5HT6, 5HT7 Ligands for uptake carriers

  42. Radioligands for NA, DA and 5HT receptors 8-OH-DPAT (5HT1A) Noradrenaline a-receptors b-receptors 7-OH-DPAT (D3) Dopamine D1,D2,D3,D4,D5 Serotonin (5-Hydroxytryptamine) ionotropic: 5HT3 metabotrop: 5HT1,5HT2, 5HT4, 5HT6, 5HT7 Ligands for uptake carriers

  43. Radioligands for NA, DA and 5HT receptors 8-OH-DPAT (5HT1A) Noradrenaline a-receptors b-receptors Dopamine Ketanserine (5HT2) D1,D2,D3,D4,D5 Serotonin (5-Hydroxytryptamine) ionotropic: 5HT3 metabotrop: 5HT1,5HT2, 5HT4, 5HT6, 5HT7 Ligands for uptake carriers

  44. Radioligands for NA, DA and 5HT receptors 8-OH-DPAT (5HT1A) Noradrenaline a-receptors b-receptors Dopamine Ketanserine (5HT2) D1,D2,D3,D4,D5 Granisetron (5HT3) Serotonin (5-Hydroxytryptamine) ionotropic: 5HT3 metabotrop: 5HT1,5HT2, 5HT4, 5HT6, 5HT7 Ligands for uptake carriers

  45. Radioligands for NA, DA and 5HT receptors 8-OH-DPAT (5HT1A) Noradrenaline a-receptors b-receptors Dopamine Ketanserine (5HT2) D1,D2,D3,D4,D5 Granisetron (5HT3) Serotonin (5-Hydroxytryptamine) ionotropic: 5HT3 metabotrop: 5HT1,5HT2, 5HT4, 5HT6, 5HT7 Ligands for uptake carriers RS 23597-190 (5HT4)

  46. Radioligands for NA, DA and 5HT receptors Nisoxetine (NA) Noradrenaline a-receptors b-receptors Dopamine D1,D2,D3,D4,D5 WIN 35428 (DA; a cocaine analogue) Serotonin (5-Hydroxytryptamine) ionotropic: 5HT3 metabotrop: 5HT1,5HT2, 5HT4, 5HT6, 5HT7 Ligands for uptake carriers Citalopram (5HT)

  47. Inhibitors; IC50, Ki, Hill coefficient A competitive inhibitor (I) displaces a ligand (L) from its binding site (B): [L] BM. [BL] = defined as BLo (in absence of I) [L] + KD

  48. Inhibitors; IC50, Ki, Hill coefficient A competitive inhibitor (I) displaces a ligand (L) from its binding site (B): [L] BM. [BL] = defined as BLo (in absence of I) [L] + KD This original value BLo is decreased by increasing [I]: [I] BL(I) = BLo – BLo. [I] + IC50

  49. Inhibitors; IC50, Ki, Hill coefficient A competitive inhibitor (I) displaces a ligand (L) from its binding site (B): [L] BM. [BL] = defined as BLo (in absence of I) [L] + KD This original value BLo is decreased by increasing [I]: [I] BL(I) = BLo – BLo. [I] + IC50 BLo. [I] + BLo. IC50 – BLo. [I] IC50 = = BLo. [I] + IC50 [I] + IC50

  50. Inhibitors; IC50, Ki, Hill coefficient The IC50 of a competitive inhibitor ...

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