110912%20Case%20Study%206%20per%20page - 9/11/11 ...

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Unformatted text preview: 9/11/11 Today’s Topics & Additional Readings Topics Reading Sedatives/Hypnotics •  Foye’s Chapter 19 General Anesthetics •  Foye’s Chapter 18 Anti-Anxiety •  Foye’s Chapter 22, pages 615 – 627 “Case” Study •  J.Med.Chem. 2011, 54, 5694-5711 Recent Medicinal Chemistry Research on Benzodiazepines PHRx 4040 Drug Design: Case Study September 12, 2011 Dr. Marcy J. Balunas Structures of New Benzodiazepines SAR for These BZDs •  Small atoms at R1 required for nM affinity •  Substituents at 4’-position cause slight affinity decrease •  Presence of H at position 8 causes antagonist-like activity •  Introduction of carbon at 4-position not tolerated 1 9/11/11 Crystal Structure of Compound 7 In vitro Efficacy (Measured as Cl-  Uptake) Full agonists increase current (flunitrazepam -  rohypnol) Antagonists have no effect (flumazenil) Inverse agonists decrease ion flow (beta- carboline) 36Cl– uptake measured in rat cerebrocortical synaptoneurosomes for compounds 5a (magenta), 5b (bleu), 5c (cyan), 5f (green), 5n (red), flunitrazepam (empty circles), flumazenil (empty diamonds), and ethyl β-  carboline (empty squares). In vivo Efficacy Light/Dark Test •  Four potential actions considered o  Anxiolytic effect screened by light/dark box test o  Myorelaxant effect measured by rotarod test o  Effect on spontaneous motility and explorative activity measured by hole-board test o  Learning and memory impairment evaluated by passive avoidance test More time in light is indicative of anxiolytic effect Light/Dark Test Negative control Rotarod Test Positive control More falls from rotating rod indicative of effects on motor coordination Anxiolytic effect. Each value represents the mean of at least 15–20 mice: (∧) P < 0.05, (∗) P < 0.01 vs saline/carboxymethylcellulose (CMC) treated mice. 2 9/11/11 Rotarod Test Negative control Effect on motor coordination 45 min after the treatment. Each value represents the mean of at least 15–20 mice: (∧) P < 0.05, (∗) P < 0.01 vs saline/CMC- treated mice. Hole Board Test Negative control Hole Board Test Number of movements ≈ spontaneous motility Number of inspections ≈ explorative activity Passive Avoidance Test Thermal shock given when entering dark compartment Mouse learns to avoid shock by suppressing behavior (repressing urge to enter dark compartment) Effects on neurological or muscular alterations. Each value represents the mean of at least 15–20 mice: (∧) P < 0.05, (∗) P < 0.01 vs saline/ CMC- treated mice. Passive Avoidance Test Scopolamine added to induce amnesiac effect and at higher doses was able to prevent amnesic effect of scopolamine Learning and memory test. Each value represents the mean of at least 15–20 mice: (∧) P < 0.05, (∗) P < 0.01 vs saline/CMC- treated mice. Effect on GABA Receptor Subtypes Diazepam causes increased action, which is blocked when 5b,c,f, or g are added (blocking is not specific to receptor subtype) Effects of compounds 5b,c,f,g (10 µ;M) on the diazepam (DZ) (1.0 µ;M) enhancement of the GABAA receptor function in Xenopus laevis oocytes expressing (a) α1β2γ2L, (b) α2β1γ2L, and (c) α5β2γ2L human GABAA receptors. Data are expressed as percentage potentiation of the response induced by GABA at EC10 and represent the mean ± SEM of two to three different oocytes. 3 9/11/11 Molecular Modeling •  Several favorable interactions shown in docking studies with benzodiazepine binding site Binding conformation of 5f in the CBR receptor as resulted from docking (A) and from subsequent molecular dynamics (B). The ligand and the interacting residues are represented as green and cyan sticks, respectively, while the protein is represented as bronze cartoon. Molecular Modeling Representation of the binding conformation of 5j in the CBR receptor at the beginning (red) and at the end (green) of the molecular dynamics simulation. During the simulation, the ligand changes its conformation, either losing or weakening key interactions with the protein. Conclusions •  Several compounds with high affinity for the central benzodiazepine receptor (CBR) were synthesized •  One compound (5f) behaved as full agonist in vitro and in vivo and was devoid of unpleasant side effects (no myorelaxation or amnesia) •  Compounds were found to interact with the GABAA receptor •  Molecular docking confirmed SAR at 4’-position (small substituents) and helped to demonstrate stable energetic profiles between 5f and the CBR What happens next??? 4 ...
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This note was uploaded on 10/08/2011 for the course PHAR 4030 taught by Professor Dr.miller during the Spring '11 term at UConn.

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