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Tailoring Drug Development in the Cholinergic Nervous System through Structural Templates Three targets: Nicotinic Acetylcholine Receptors (nAChR) ~15.

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Presentation on theme: "Tailoring Drug Development in the Cholinergic Nervous System through Structural Templates Three targets: Nicotinic Acetylcholine Receptors (nAChR) ~15."— Presentation transcript:

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2 Tailoring Drug Development in the Cholinergic Nervous System through Structural Templates Three targets: Nicotinic Acetylcholine Receptors (nAChR) ~15 subunits in various pentameric permutations Acetylcholinesterase (AChE) Alternatively spliced single gene Neuroligin and Neurexin Synaptic adhesion molecules

3 in situ, Click-Chemistry Leads to Drug Candidates (1) in situ Azide-Alkyne Cycloaddition on WT AChBPs Triazole Regioisomer Identification (2) in situ Azide-Alkyne Cycloaddition on MT AChBPs Cu ++ /Ru ++ catalyzed lead synthesis in microarray AChBP H 3 -Radioligand Binding Assay (SPA), K d Whole Cell Binding Assay with nAChRS (SPA), K d X-Ray Structure with AChBPs Interaction Energy with crystallographic model Binding poses, potential interacting residues Receptor Subtype Occupation Concentration dependence functional responses Receptor Selectivity Agonism (EC 50 ) or Antagonism (K A )

4 Novel Drug Discovery & Development Synthesis by in situ freeze-frame, click chemistry Physical analysis of lead complexes (binding energy, conformational changes, X-ray crystallography) Catalytic synthesis at the milligram level (refinement of SAR is done in microarrays and only leads are taken forward). Quantitate affinity and activity in vitro Assay cellular toxicity and efficacy Efficacy in intact animals Pharmacokinetic studies of disposition in the target tissues (CNS) and plasma

5 Mechanism and Therapeutic Indications Acetylcholinesterase Mechanism Antidotal Action at CNS and skeletal muscle targets Scavenging in environment, portals of entry & circulation Therapeutic Indications Organophosphate pesticide toxicity Nerve agents in terrorism Nicotinic Acetylcholine Receptor Mechanism Agonist, Partial Agonist and Antagonist Activity at nAChRs. Allosteric Modifiers at nAChRs Therapeutic Indications Disorders of nervous system development & aging dementias Tobacco cessation

6 AChE and AChBP Crystal Structures Scott Hansen Ryan Hibbs Todd Talley Akos Nemecz Kasia Kaczanowska* Zoran Radic’* Jean-Pierre Changeux* Pascale Marchot (Marseille)* Yves Bourne (Marseille)* Michal Harel (Weizmann)* Pharmacokinetics & Disposition Zoran Radic* Jeremiah Momper* Edmund Capparelli* AChE and AChBP Crystal Structures Scott Hansen Ryan Hibbs Todd Talley Akos Nemecz Kasia Kaczanowska* Zoran Radic’* Jean-Pierre Changeux* Pascale Marchot (Marseille)* Yves Bourne (Marseille)* Michal Harel (Weizmann)* Pharmacokinetics & Disposition Zoran Radic* Jeremiah Momper* Edmund Capparelli* Click Chemistry TSRI K. Barry Sharpless* Valery Fokin* Rakesh Sit* Timo Weide Joseph Fotsing Neil Grimster M.G. Finn, Georgia Tech* Kasia Kaczanowska* Gabi Amitai (IIBR) Click Chemistry TSRI K. Barry Sharpless* Valery Fokin* Rakesh Sit* Timo Weide Joseph Fotsing Neil Grimster M.G. Finn, Georgia Tech* Kasia Kaczanowska* Gabi Amitai (IIBR) Acetylcholine Binding Protein Scott Hansen Todd Talley Ryan Hibbs Zoran Radic’* Ákos Nemecz* John Yamauchi* Nan Arunrungvichian* Bill Chen* Andy McCammon(UCSD) Jon Lindstrom (Penn) David Johnson (UC, Riverside) Steve Sine (Mayo, Rochester) John Casida (UC, Berkeley) Jordi Molgo (Gif-sur-Yvette) Mike McIntosh (Univ. of Utah) Toto Olivera (Univ. of Utah) Manjunatha Kini (NUS) Acetylcholine Binding Protein Scott Hansen Todd Talley Ryan Hibbs Zoran Radic’* Ákos Nemecz* John Yamauchi* Nan Arunrungvichian* Bill Chen* Andy McCammon(UCSD) Jon Lindstrom (Penn) David Johnson (UC, Riverside) Steve Sine (Mayo, Rochester) John Casida (UC, Berkeley) Jordi Molgo (Gif-sur-Yvette) Mike McIntosh (Univ. of Utah) Toto Olivera (Univ. of Utah) Manjunatha Kini (NUS)

7 Peripheral site Active center Active center gorge

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9 Reactivation of native peripheral AChE Oxime-assisted Catalytic OP hydrolysis in Plasma Plasma Site of Exposure Alveolar Membrane Blood-Brain BarrierCNS

10 Reactivation of native peripheral AChE Oxime-assisted Catalytic OP hydrolysis in PlasmaCNSPlasma Site of Exposure Alveolar Membrane Blood-Brain Barrier x

11 Reactivation of native peripheral AChE Oxime-assisted Catalytic OP hydrolysis in PlasmaCNSPlasma Site of Exposure Alveolar Membrane Blood-Brain Barrier H + + x Oxime Reactivation of native AChE in CNS H + +

12 AChBP: a structural surrogate of the nAChR Ligand Binding Domain Hansen, S. et. al Brejc, K. et. al subunits each of which have: I.A large extra cellular domain II.4 membrane-spanning regions III.α β combinations make up most neuronal receptors

13 Nicotine Anabaseine Epibatidine Cytisine Anatoxin-a d-Tubocurarine MLA SPX GYM DMXBATropisetronGranisetron Lobeline Sazetidine A  Conotoxin Waglerin  cobratoxin


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