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CHEM E-120 Harvard University Extension School Spring 2011

CHEM E-120 Harvard University Extension School Spring 2011. Disorders of Mood and Behavior Anxiety Classical Benzodiazepines – GABA A Allosteric Modulators Partial Agonists Subtype Selective Benzodiazepines – α2/α3 5-HT 1A agonist. Anxiety. A normal response to threatening situations

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CHEM E-120 Harvard University Extension School Spring 2011

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  1. CHEM E-120Harvard University Extension SchoolSpring 2011 Disorders of Mood and Behavior Anxiety Classical Benzodiazepines – GABAA Allosteric Modulators Partial Agonists Subtype Selective Benzodiazepines – α2/α3 5-HT1A agonist CHEM E-120

  2. Anxiety A normal response to threatening situations Key feature is increased fearfulness accompanied by subjective (heightened sense of awareness to a deep fear of impending disaster and death) and physiological manifestations. Panic Disorder (DSM-IV 300.01) Post-traumatic stress disorder (PTSD, DSM-IV 309.81) Generalized Anxiety Disorder (GAD, DSM-IV 300.02) Social phobia (DSM-IV 300.23) Obsessive-compulsive disorder (OCD, DSM-IV 300.3) Anxiety and depression often occur together (comorbidity) e.g. 50% of patients with panic attacks have depression Most common of psychiatric disorders, 10-30% of population CHEM E-120

  3. Neurobiology of Anxiety Animal models of fear and avoidance1 Fear network has been proposed centered on the amyglada2 Sensory thalamus cortex hippocampus memory, learning dopaminergic noradrenergic serotonergic cholinergic amyglada Hypothalamus HPA axis periaqueductal gray region axis autonomic response (fight or flight) Locus cerules NE, CRH Main Neurotransmitters are GABA (inhibitory) and Glutamic Acid (excitory) Animal Models of Anxiety… Trends in Pharmacological Sciences 2008, 29, 493 Neuroanatomical Hypothesis of Panic Disorder, American J. Psychiatry 2000, 157, 493 CHEM E-120

  4. Therapeutic Targets – Approved AnxiolyticsBenzodiazepines Allosteric modulators of GABAA ligand-gated Cl- ion channel where they increase the influx of Cl-, leading to hyperpolarization – reduction in neuronal activity Allosteric modulation – a drug binds to a different site on a protein than where GABA binds, changing the conformation of the ion channel, increasing the affinity of GABA. Positive Cooperativity. Alprazolam (Xanax) Panic Disorder, Social Phobia Chlordiazepoxide (Librium) Anxiety Clonazepam (Klonopin) GAD, Panic Disorder, Social Phobia Diazepam (Valium) Anxiety Side effects Sedation, dose-related transition anxiolytic  sedative Addiction – mild Memory impairment - Rohypnol (flunitrazepam) date rape Lyrica (Pfizer) not approved for GAD CHEM E-120

  5. Benzodiazepines CHEM E-120

  6. GABAA Ion Channels Ion channel is pentameric structure where each pentamer subunit is composed of four polypeptides, 19 subtypes. Known the benzodiazepines (BZ) bind to sites on the interface of  and  subunits. GABA binds to 2 sites on  subunits. Currently thought that the BZ binding site involves a combination of 1, 2, 3 or 5 + 2 or 3. 1 thought to play a role in amnesia and sedative effects of BZ 21 and 32 thought to be most important for anxiolytic effects of BZ 5 memory component? Barbiturates and alcohol also bind to GABAA Zolpidem (Ambien) binds to GABAA 1 Science 2000, 290(5489)131 (transgenic mice) 2 Journal of Neuroscience 2005, 25(460 10682 CHEM E-120

  7. Approved Nonbenzodiazepine Anxiolytics Sertonergic System SSRI’s Sertraline (Zoloft) Panic disorder, OCD, PTSD, social phobia Fluoxetine (Prozac) OCD 5-HT1A agonist Buspirone (BuSpar) GAD Noradrenergic System Yohimbine blocks α2 adrenergic autoreceptors (activation inhibits noradrenergic neuronal activity) activating noradrenergic activity – induces panic attacks NSRI Venlafaxine (Effexor) GAD CHEM E-120

  8. GABAA – Benzodiazepines (BZ) Benzodiazepines first discovered in 1957, found to have potent anxiolytic activity in animal models of sedation. No binding assays, went directly from flask into animal models Librium inclined screen – muscle relaxation & sedation foot shock induced aggression in mice and rats – taming effect cat – muscle relaxation pentylenetetrazole – sedation & anticonvulsant Later found to bind to the GABAA Cl- ion channel allosteric binding increases binding affinity of GABA CHEM E-120

  9. BZ potentiate Cl- influx Addition of BZ triples amplitude GABA invokes 0.9 nA current response Chemicals delivered to cultured mouse spinal cord neuron voltage-clamped at -70 mV with a microelectrode. CRC Press GABA and benzodiazepine Receptors Vol 1 1988 CHEM E-120

  10. Benzodiazepine Potencies Correlation between receptor affinity and behavioral potency among various benzodiazepines. Benzodiazepines were tested for their potency (Ki) in displacing [3H]diazepam from specific BDZ binding sites on rat cerebral cortical membranes. The resulting values were highly correlated (r=.90, p<.0001) with the behavioral potency of the same drugs (EDmin) in the cat muscle relaxant test. CHEM E-120

  11. Benzodiazepine SAR tolerant of substituents HBA critical - stacking van der waals C7 electronegative group tends inc func anxiolytic activity C3 substitution decreases antagonist activity but not agonist activity Not required for in vitro binding but is for in vivo efficacy 4’ very sensitive to substitution CHEM E-120

  12. Synthesis of Benzodiazepines 2-aminoaryl ketones CHEM E-120

  13. Pharmacophore • Those parts of the drug molecule that interact with the protein: key interactions that are responsible for the biological activity of the drug. • Medicinal Chemists commonly refer to the pharmacophore as consisting of a scaffold (core) pendant functional groups bioactive conformation (i.e. the sterochemistry). • A pharmacophore does not necessarily represent a real molecule. dad d a dac dab dcd abc bcd etc b c dbc CHEM E-120

  14. Ligand-based Drug Design In structure-based computerized drug design, the 3D structure of the Target and drug should be known with a high degree of resolution. The exact 3D structure of most receptors is not know. Series of assayed ligands Generate energy-minimized structures – molecular mechanics Calculate various properties - descriptors Determine if a common set of shape or descriptors describe the ensemble - pharmacophore CHEM E-120

  15. Theoretical Methods Molecular Mechanics Treats atoms as balls and bonds as springs - classical mechanics Assigns x,y,z coordinates to atoms in a molecule and calculates the potential energy at positions Force Field: collection of values that define the change in energy with geometry Force fields can be transferred from one molecule to another to predict geometry. calculate the potential energy of a conformation Methods: MM1, MM2, AMBER, OPLS Quantum Mechanics Represents molecules in terms of their electron distribution The shapes of orbitals (sp3, sp2, sp, π) and the electron distribution derive from QM. partial atomic charges (areas of high and low electron density) electrostatic potential dipole moments (polar bonds) Methods: MINDO, ZINDO, PM3 QSAR (Quantitative Structure Activity Relationships) combine aspects of both size & charge CHEM E-120

  16. Descriptors of Molecules CHEM E-120

  17. Generating the Pharmacophore Usually some type of iterative process where a compound(s) a model Is developed. A training set of compounds is overlayed and the fit quantified by a scoring function. This is used to predict the biological activity (Ki) for a set of compounds and compared to the known values. The model is then adjusted as needed. CHEM E-120

  18. Intermolecular Bonding Hydrophobic Pocket CHEM E-120 Salt bridge

  19. Benzodiazepine Binding Models Relative locations of the descriptors and regions of the unified pharmacophore/ receptor model. The pyrazolo[3,4-c] quinolin-3-one CGS- 9896 (dotted line), a diazadiindole (thin line), and diazepam (thick line) aligned within the unified pharmacophore/receptor model for the Bz BS. H1 and H2 represent hydrogen bond donor sites within the Bz BS A2 represents a hydrogen bond acceptor site necessary for potent inverse agonist activity in vivo. L1, L2, L3 and LDi are four lipophilic regions S1, S2, and S3 are regions of negative steric repulsion. LP = lone pair of electrons on the ligands Current Medicinal Chemistry, 2007, 14, 2755-2775 CHEM E-120

  20. Benzodiazepine Binding Models CHEM E-120

  21. Benzodiazepine Binding Models Current Med Chem 2007, 14, 2755 CHEM E-120

  22. Receptors/Drugs - Partial Agonists Emax of partial agonist [A]2 [A]1 epartial agonist = CHEM E-120

  23. Alprazolam (Xanax) This type of modification is leading into new nonbenzodiazepines that bind selectively to the 2 site and/or are partial agonists BZ use is limited by side effects, e.g., sedation and amnesia, the development of tolerance, and concerns about dependence and withdrawal. These side effects are a natural extension of their mechanism of action. Considerable effort has been expended over the past three decades to discover and develop novel, anxioselective BZ ligands that have improved side effect profiles. (Comprehensive Medicinal Chemistry II Chapter 6.04) CHEM E-120

  24. New Approaches towards GABAA - Partial Agonists Clinical trials for GAD and panic disorder but sedative EC50 = 3-10 M Similar to diazepam Phase III but liver toxicity Low nM No tolerance to anxiolytc effect, no withdraw, lower abuse potential CHEM E-120

  25. New Approaches towards GABAA - Subtype Selective Low nM at 1,2,3,5 3 full agonist 1,2,5 partial agonist 1,2,3 selective 1,5 partial agonist 2,3 full agonist Ki similar but no efficacy at 1 CHEM E-120

  26. 2/3 selective example - Merck Ki (nM) Efficacy (1.0) 1 = 1.5 -7% (antagonist) 2 0.12 3 = 8.5 0.44 5 = 12.1 0.01 CHEM E-120

  27. Serotonergic System in Anxiety Agonists for 5-HT1A receptor presynaptic (autoreceptor) in raphe nuclei could contribute to delayed onset. Buspirone (Buspar) is a 5-HT1A partial agonist approved for GAD. Nonsedative Ineffective in patients who have previously taken benzodiazepines. Delayed onset Buspirone has no significant affinity for benzodiazepine receptors and does not affect GABA binding in vitro or in vivo when tested in preclinical models. Buspirone has moderate affinity for brain D2-dopamine receptors. Some studies do suggest that buspirone may have indirect effects on other neurotransmitter systems. CHEM E-120

  28. 5-HT1A Selective Compound Selectivity problems versus 1-anderergic receptor High homology (45%) in transmembrane amino acid sequences of 5-HT1A and 1-anderergic receptors To design compounds with selectivity for 5-HT1A versus 1 synthesized a training set of 32 compounds based on the structure below. The structural field of compoundsVIis defined with6 parameters: three indicator variables (IA,IBandIn)size of the A and B rings and n lipophilic () electronic σo- or σm- steric (MR) Used to pick the R groups from a set of 387 substituents. J. Med. Chem 2001, 44, 186 CHEM E-120

  29. 5-HT1A Selective Compound J. Med. Chem 2001, 44, 186 CHEM E-120

  30. 5-HT1A Selective Compound n = 4 m = 0,1 J. Med. Chem 2001, 44, 186, 198 CHEM E-120

  31. 5-HT1A Selective Compound n = 4 favors 5-HT1A ring size no effect ortho no effect Meta-position m-bromo or m-amino group (VW(Br) = 17.2 Å3; VW(NH2) = 11.4 Å3) leads to compounds with the same affinity at both receptors. A trifluoromethyl group (VW = 24.2 Å3) at this position leads to an increase in the 5-HT1A selectivity (compound 28: 26-fold). Best selectivity ratio is reached with the most voluminous group, a m-NHCOPri (VW = 70.8 Å3) which leads to the most selective compounds 20 and 32 (98- and 59-fold, respectively). J. Med. Chem 2001, 44, 186, 198 CHEM E-120

  32. 5-HT1A Selective Antagonist QSAR Pharmacology No effect of mouse rectal temp Blocked hypothermia induced by 8-OH-DPAT (5-HT1A agonist) No affect on behavioral tests but blocked effects of 8-OH-DPAT 5-HT1A antagonist D2 antagonist J. Med. Chem 2001, 44, 186 CHEM E-120

  33. 5-HT1A Selective Antagonist Developed a QSAR model based on Hansch Analysis and Neural Networks to design compounds with selectivity for 5-HT1A versus 1 Used the training set of 32 compounds. Each chemical structure defined with9 descriptors: three indicator variables (IA,IBandIn)size of the A and B rings and n lipophilic (o and m) electronic [field (F) and resonance (R)] position and nature of R. steric van der Waals (Vo, Vm) Hansch Analysis 5-HT1A pKi = 7.55 – 0.251IA – 0.762IN=3 + 1.73F – 0.0292Vo – 0.0193Vm + 1.26o 1 pKi = 7.68 – 0.272IB + 1.32F – 0.0306Vo – 0.0417Vm + 1.17o lead to: J. Med. Chem 2001, 44, 198 CHEM E-120

  34. 5-HT1A Selective Agonist 5-HT1A Ki = 27 nM antagonist 1 > 1000 nM affect 1 5-HT1A more tolerant  5-HT1A Ki = 4.1 nM agonist 1 > 1000 nM JMC 2005, 48, 2548 CHEM E-120

  35. 5-HT1A Selective Agonist (S)-9 J. Med. Chem 2005, 48, 2548 CHEM E-120

  36. 5-HT1A Selective Agonist CHEM E-120

  37. 5-HT1A Selective Agonist CHEM E-120

  38. 5-HT1A Selective Agonist Ionic piperizine N - Asp Van der waals aromatic-aromatic Trp and Phe H-bonds Thr, Ser, Trp CHEM E-120

  39. Future Targets Transient Receptor Potential Channel 5 (TRPC5) mice in which TRPC5 gene was deleted showed diminished fear levels in anxiety models. Highly expressed in amygdala Cell. 2009 May 15;137(4):761-72 CRF1 antagonists – shown to produce anxiolytic effects Neurokinin-2 (NK2) antagonist – Saredutant (SR48968) in Phase 3 trials for GAD. Less side effects than SSRI’s but relapse not significantly reduced (MDD) Metabotropic (GPCR) glutamate receptors – mGlu 2 agonists, mGlu 1 antagonists beta 3 receptor agonist – given after trauma, reduce memory of traumatic events (PTSD) V1b receptor antagonist – vasopression peptide in HPA, found in amygdala NK3 – NK2 receptor antagonist CHEM E-120

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