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CHEM E-120 Harvard University Extension School

CHEM E-120 Harvard University Extension School. Disorders of Mood and Behavior Schizophrenia Antipsychotic Drugs 3/9/2011. Schziophrenia. 1. Two or more for a one month period Delusions Hallucinations Disorganized speech Grossly disorganized or catatonic behavior

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CHEM E-120 Harvard University Extension School

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  1. CHEM E-120Harvard University Extension School Disorders of Mood and Behavior Schizophrenia Antipsychotic Drugs 3/9/2011 CHEM E-120

  2. Schziophrenia 1. Two or more for a one month period Delusions Hallucinations Disorganized speech Grossly disorganized or catatonic behavior Continuous symptoms must persist for 6 months Three domains Positive Symptoms: excess or distortion of normal function (psychosis) Negative Symptoms: decrease or loss of normal function (social withdrawal) Cognitive Impairment: information processing CHEM E-120

  3. Neurochemical Hypotheses of Schizophrenia Dopamine Hyperfunction Hypothesis Hyperactivity of the dopaminergic system in the forebrain increases levels of dopamine. Proposed based on the observation that antipsychotic drugs tend to bind to D2 receptor as antagonists or inverse agonists. Serotonin (5HT) Hypothesis Decrease in serotonin function, 5HT2a antagonist/inverse agonist Clozapine Hypothesis: mixed levels of D2/5HT2/H1/M1/adrenergic activity Glutamate Hypofunction Hypothesis: NMDA blockade, decreased activation of NMDA receptors GABA Hypothesis: GABAergic system appears perturbed, lower levels of GABA reuptake sites CHEM E-120

  4. Neurotransmitters - Dopamine 2 families of dopamine binding receptors D1-like increase cAMP, increased concentration in prefrontal cortex schizophrenia D1 caudate/putamen, NuAcc, cerebral cortex D5 located in hippocampus, hypothalamus, cerebral cortex very high affinity for dopamine reduced agonist induced locomotion, startle, and prepulse inhibition D2-like decrease cAMP, open K+ channels, close Ca2+ channels D2 caudate/putamen, NuAcc knockout mice parkinsonian-like motor impairment D3 hypothalamus D4 frontal cortex, NuAcc knockout mice hypersensitive to ethanol and stimulants CHEM E-120

  5. Neurotransmitters - Serotonin Binds to the serotonin receptors and transporter Important in depression, anxiety, and schizophrenia 3 main families 5-HT1 - GPCR, 5 subtypes (A, B, D, E, F) have 40-60% sequence homology, inhibit adenylyl cyclase 5-HT1A – cortical and limbic structures, presynaptic (autoreceptors) and postsynaptic 5-HT2 - GPCR, 3 subtypes (A, B, C) have 45-50% sequence homology, stimulate phospholipase C 5-HT2A – frontal cortex, parts of limbic system, site of action of hallucinogenic drugs 5-HT2C – limbic system and motor system, site of action of hallucinogenic drugs 5-HT3 - ligand-gated ion channel, 6 subtypes, stimulate adenylyl cyclase CHEM E-120

  6. Antipsychotic Drugs First generation antipsychotics (FGA) introduced 1955. Tend to be D2 antagonists Chlorpromazine (Thorazine) Second generation antipsychotics (SGA, atypical antipsychotics) D2 antagonist/5-HT2a antagonist Haloperidol Clozapine (Clozaril) Olanzapine (Zyprexa) Quetiapine (Seroquel) Risperidone (Risperdal) Antipsychotics are atypical when their 5-HT2A antagonism superimposed on D2 antagonism reduces D2 binding of the drug enough to reverse motor side effects but not enough to reverse antipsychotic effects. New drugs: Aripiprazole - partial agonist CHEM E-120

  7. Schizophrenia Neurocircuitary Dopamine Serotonin Norepinephrine Cortex striatum: caudate nucleus (cognition), putamen (motor), nucleus accumbens Cortex Caudate nucleus HC - hippocampus Thalumus Putamen NuAcc HC HYPTh VTA Am SN Locus coeruleus Raphe nuclei A9 - Substantia nigra - extrapyramidal nigrostriatal pathway A10 – Ventral tegmental area mesolimbic pathway (positive symptoms) mesocortical pathway (negative symptoms) CHEM E-120

  8. Modified Dopamine HypothesisNormal State Prefrontal cortex Limbic area striatum Negative feedback inhibitory Mesocortical system Mesolimbic system Brainstem dopaminergic neurons Ventral tegmantal area (A10) Kandel p 1205 CHEM E-120

  9. Modified Dopamine Hypothesis - Schizophrenic State Prefrontal cortex Decreased activity Reduction in dopamine levels D1 highly expressed Produces Negative symptoms Limbic area (striatum) Increase in activity Increase in dopamine levels Produces Positive symptoms (psychosis) Loss of negative feedback Mesocortical system disrupted Mesolimbic system Brainstem dopaminergic neurons Ventral tegmantal area (A10) CHEM E-120

  10. Modified Dopamine HypothesisSchizophrenic State and EPS (side effect) Limbic area + striatum Increase in activity Increase in dopamine levels, high expression levels of D2, D3, and D4 Positive symptoms Nigrostriatal system motor control side effects D2 antagonists cause EPS Mesolimbic system A10 VTA (A10) SN (A9) EPS – extrapyramidal syndrome (involuntary movements, muscular rigidity) CHEM E-120

  11. Serotonin - Dopamine Hypothesis - Schizophrenic State Prefrontal cortex Decreased activity Reduction in dopamine levels Negative symptoms Limbic area (striatum) Increase in activity Increase in dopamine levels Positive symptoms Mesocortical system disrupted Mesolimbic system Raphe nuclei 5-HT Brainstem dopaminergic neurons CHEM E-120

  12. Serotonin - Dopamine Hypothesis - Schizophrenic State CNS Drugs 2006, 20, 389 Prefrontal cortex (dopamine) 5-HT2A antagonist DA 5-HT1A agonist DA 5-HT2C antagonist DA Limbic area + striatum dopamine levels 5-HT2A antagonist dec dopamine (A10) 5-HT2c antagonist inc dopamine 5-HT1A agonist (inhibit neuron, activating dopamine neurons, dec EPS) Raphe nuclei 5-HT 5-HT2A antagonist (disinhibits dopaminergic neuron, increased dopamine binds to D2 preventing binding of drug antagonists, thereby dec EPS) Substantia nigra (A9) Modulation of 5-HT2A, 5-HT1A, or 5-HT2C alone have no antipsychotic effectt CHEM E-120

  13. Antipsychotic Drugs First generation antipsychotics (FGA) introduced 1955. Tend to be D2 antagonists Chlorpromazine (Thorazine) Second generation antipsychotics (SGA, atypical antipsychotics) D2 antagonist/5-HT2a antagonist Haloperidol Clozapine (Clozaril) Olanzapine (Zyprexa) Quetiapine (Seroquel) Risperidone (Risperdal) Antipsychotics are atypical when their 5-HT2A antagonism superimposed on D2 antagonism reduces D2 binding of the drug enough to reverse motor side effects but not enough to reverse antipsychotic effects. New drugs: Aripiprazole - partial agonist CHEM E-120

  14. D2 occupancy Major side-effect of FGA is extrapyramidal effects (Parkinson-type effects) due to D2 antagonism. D2high and D2low states have been proposed where D2high is a high affinity state of the D2 receptor. Suggested an elevation of D2high occurs leading to hypersensitivity to dopamine. Theory - drugs compete with dopamine for D2 sites, ideal antipsychotic efficacy w/o EPS achieved by < 80% occupancy and fast dissociation Drug + D2 [Drug][D2] (therapeutic effect) DA + D2 [DA][D2] (EPS effect) ~ 40% occupancy CHEM E-120

  15. First Generation Antipsychotics Naunyn-Schmiedeberg’s Arch Pharmacol 1984, 327, 95 CHEM E-120

  16. Structures of FGA/SGA Antipsychotic FGA D2 potency SGA benzazepines - Similar D2 (efficacy) + 5-HT2A (efficacy/reduce EPS) CHEM E-120

  17. Clozapine Introduced in 1972 Withdrawn in 1975 (agranulocytosis, loss of white blood cells) Reintroduced with restrictions in 1990 First “atypical” antipsychotic as it did not produce extrapyramidal side effects. Study of clozapine lead to 5-HT2a/D2 hypothesis: To overcome side effects of chloropromazine: i.e. better binding affinty at 5-HT2a than D2 Ki 5-HT2a Ki D2 < 1.0 CHEM E-120

  18. Clozapine Ki 5-HT2a Ki D2 < 1.0 CHEM E-120

  19. Receptors and Effects CNS Drugs 2008 22, 1047 CHEM E-120

  20. Newer Atypical Antipsychotics CHEM E-120

  21. Atypical Antipsychotics Binding Data MARTA – multiacting receptor-targeted antipsychotic, SDA – serotonin-dopamine antagonist CHEM E-120

  22. Animal Behavioral Models Conditioned avoidance The ability of a compound to inhibit the conditioned avoidance response (CAR) to an aversive stimulus is one of the oldest predictors of antipsychotic efficacy. In this test, rats are trained to move from one side of shuttle box to the other on presentation of an audible cue (the conditioned stimulus) in order to avoid a footshock (the unconditioned stimulus). Once the animals have been trained, both typical and atypical antipsychotics are effective in decreasing the CAR to the conditioned stimulus without altering the escape response elicited by the unconditioned stimulus. This inhibition of the CAR is thought to be mediated by a reduction in dopaminergic function in the striatum and nucleus accumbens. Therefore, inhibition of CAR is not an actual preclinical model of schizophrenia, but rather a facile in vivo method of detecting DA receptor blockade. The comparison between doses of antipsychotics that inhibit CAR and doses that induce catalepsy provides a convenient method to determine thetherapeutic index for EPS. CHEM E-120

  23. Animal Behavioral Models Locomotor activity Practically all antipsychotic agents decrease spontaneous locomotor activity and decrease locomotor activity that has been pharmacologically increased by amphetamine, PCP 2, or apomorphine. As described for CAR, decreased locomotor activity can be interpreted as an in vivo readout of DA antagonism. However, the ability of nondopaminergic agents to induce hyperlocomotion that is sensitive to antipsychotics, and the ability of novel nondopaminergic compounds to reduce hyperlocomotion elicited by amphetamine suggest that this particular model involves a more complex circuit that may possibly have some relevance to the clinical state. CHEM E-120

  24. Animal Behavioral Models Latent inhibition Latent inhibition is the ability of a pre-exposed nonreinforced stimulus to inhibit later stimulus-response learning. This behavior can be disrupted by amphetamine in both rodents and humans. While often put forward as a model of positive symptoms with significant face validity, a careful review of the literature reveals significant disagreement on key facts, including the prevalence of disrupted latent inhibition in schizophrenic patients, the responsiveness of amphetamine-disrupted latent inhibition to atypical antipsychotics, and key differences between experimental paradigms used in human and animal studies. Results employing the latent inhibition assay must be interpreted with caution until these controversies are fully addressed. CHEM E-120

  25. Animal Behavioral Models Prepulse inhibition A disruption in sensory and cognitive gating is hypothesized to be at the core of many of the symptoms of schizophrenia. Prepulse inhibition (PPI) refers to the ability of a low-intensity stimulus, or prepulse, to diminish the startle response elicited by a higher-intensity stimulus. This model has gained significant favor in recent years largely due to the findings that schizophrenic patients exhibit deficits in sensory and cognitive gating. This is particularly evident in studies of event-related potentials (ERPs) in the electroencephalogram of schizophrenic patients. These differences in ERPs suggest that schizophrenic patients have a deficit in the gating or processing of sensory information. This impaired sensorimotor gating may underlie the vulnerability in schizophrenia to sensory flooding, cognitive fragmentation, and conceptual disorganization. PPI is disrupted by a wide range of psychotomimetics and can be rescued by treatment with antipsychotic drugs. Based on the high degree of face validity, apparent predictive validity, and the ability to strengthen construct validity by disrupting the behavior with multiple classes of psychotomimetics, PPI stands out as the current ‘gold standard’ assay for evaluating animal models of schizophrenia. CHEM E-120

  26. CATIE - 2005 Large scale clinical trial sponsered by NIH involving 1493 patirents at 57 sites (NEJM 2005, 353, 1209). Patients were randomely assigned to olanzapine (7.5 - 30 mg/day) SGA perphenazine (8 - 32 mg/day) FGA quetiapine (200 - 800 mg/day) SGA risperidone (1.5 - 6 mg/day) SGA ziprasidone (40 - 160 mf/day) SGA 74% discontinued use before 18 months due to side-effects or lack of efficacy. Judged that in terms of efficacy and patient compliance SGA may be no better that FGA Calls into question the entire D2/5-HT2A approach CHEM E-120

  27. Aripiprazole D2 and 5-HT1A partial agonist Approved for use in USA 2002. Efficacy against positive and negative symptoms. Same rate of EPS (21%) as placebo(19%) vs haloperidol(43%) 90% bioavialable t1/2 = 75 hours, 94 hrs active metabolite 10-15 mg/day maintenance dose 10 - 30 mg/day CHEM E-120

  28. Aripiprazole Partial agonists Low levels of endogenous full agonist - partial agonist active High levels “ - partial agonist = antagonist In PFC will act as agonist relieving negative symptoms In limbic/striatum will act as antagonist relieving pos symptoms CHEM E-120

  29. Discovery of Aripiprazole Chem. Pharm. Bull 1988, 36, 4377 Otsuka Pharmaceutical Co. Developed into several drugs Looking for anti-histimine drugs w/o CNS side effects Neuroleptic-like activity in rodent screen and did not have EPS This compound was used as a lead to explore the development of antipsychotics with fewer side effects No Dopamine receptor antagonism Inhibition of DA release from presynaptic neurons or inhibit DA synthesis CHEM E-120

  30. Discovery of Aripiprazole Chem. Pharm. Bull 1988, 36, 4377 Otsuka Pharmaceutical Co. n = 1-4 22 mono and disub benzene rings Prepared 34 compounds and compared to chlopromazine and haloperidol Dopamine induces jumping behavior in mice 1. Inhibition of L-DOPA induced jumping (L-DOPA converted to DA) 2. Inhibition of methamphetamine-induced jumping (DA releaser) 3. EPS side effects measured by induction of catalepsy in mice CHEM E-120

  31. Discovery of Aripiprazole Inhibition of jumping behavior No -adrenergic antagonism (side effects) 8>7>>6>5 5>6,7>8 Inhibition of jumping behavior n = 3 ≥ 4 >> 2,5 CHEM E-120

  32. Discovery of Aripiprazole Inhibition of jumping behavior 1-2 substituents found to enhance activity 2,3-dichloro reduced activity ED50 37 mg/kg 2-CH3 ED50 0.7 mg/kg 2,3-diCH3 ED50 1.2 mg/kg 2-F ED50 1.9 mg/kg Induction of catalepsy in mice < chlorpromazine and haloperidol CHEM E-120

  33. Discovery of Aripiprazole Autoreceptor Agonist effects Was in clinical trials but stopped Aggravated positive symptoms In some patients CHEM E-120

  34. Discovery of Aripiprazole Postsynaptic DA receptor antagonist: ability to inhibit APO-induced sterotypic behavior (locomoter activity) in mice (anti-APO test) Presynaptic DA autoreceptor agoinst activity: ability to reverse the increase in DOPA synthesis induced by GBL (gamma-butyrolactone) J Med Chem 1998, 41, 658 CHEM E-120

  35. Discovery of Aripiprazole ED50mol/kg po (anti-APO test) 41 26 17 2.8 >23 Butoxy chain best CHEM E-120

  36. Discovery of Aripiprazole Anti-APO test ED50mol/kg po If 2 = CH3, at 3 Cl = Br >F If 2 = CH3, electron-withdrawing at 3 increases potency electron-releasing at 3 decreases potency 2-CH3,3-Cl ED50 = 2.8 mol/kg po 2-Cl, 3-CH3 ED50 = 0.9 mol/kg po 2,3-(Cl)2 ED50 = 0.6 mol/kg po 2,4 >7.0 2,5 2.7 2,6 >7.0 3,4 >7.0 3,5 1.1 CHEM E-120

  37. Discovery of Aripiprazole Anti-APO test Position ED50mol/kg po 5 >22 6 >22 7 0.6 8 >22 SAR results for Postsynaptic DA receptor antagonism Side chain C4 > C3 and C5 1-2 substituents on aromatic ring 2-OCH2CH3 best for 1 substituent 2,3-dichloro best for 2 substituents Substitution at position 7 of 3,4-dihydroquinolinone ring is best CHEM E-120

  38. Discovery of Aripiprazole ED50mol/kg po Inhibit GBL Induced DOPA synthesis B/A adverse effect beneficial effect measurement of peripheral activity CHEM E-120

  39. Discovery of Aripiprazole Time course of inhibition of APO-induced sterotypy at 1-6 hours after 30mg/kg po No inhibition Maximum inhibition at 2 and 4 hrs after admin. ED50 49 mol/kg Complete inhibition at 2 hours ED50 11.8 mol/kg CHEM E-120

  40. Discovery of Aripiprazole Antagonist activity Agonist activity JPET 1995, 274, 329 CHEM E-120

  41. Metabolism of Aripiprazole Aripiprazole OPC-14857 Ki (nM) ReceptorAripiprazoleOPC-14857 5-HT2A 7.9 2.5 5-HT2C 126 63 D2 1 0.5 D3 10 20 5-HT6 100 79 European J Pharmacology 2006, 546, 88 CHEM E-120

  42. Metabolism of Aripiprazole Full agonist EC50 1.5 nM EC50 4.7 nM CHEM E-120

  43. Bifeprunox (DU-127090) - Solvay D2 Ki = 3.2 nM partial agonist (28% at 1M) 5-HT1A Ki = 10 nM partial agonist, D3 Ki = 0.6 nM D4 Ki = 1.6 nM PET imaging at 10mg, 90% occupancy of striatal D2 after 2 hours Not approved by FDA in 2007 due to lack of efficacy CHEM E-120

  44. D2 antagonist/5-HT1A agonist Tried to mimic (bioisostere) Biphenyl methylamine but could not Biphenyl critical CHEM E-120

  45. D2 antagonist/5-HT1A agonist CHEM E-120

  46. D2 antagonist/5-HT1A agonist 20 16 CHEM E-120

  47. D2 antagonist/5-HT1A agonist 5-HT1A/D2 Flat-body syndrome Potency to induce catalepsy Inhibition of methyl phenidate (indirect DA agonist) induced stereotypy & hyperlocomotion Lower lip retraction 5-HT1A agonist 1.1 - 8.3 mg/kg - range of 5-HT1A agonism to achieve antipsychotic effects w/o negative 5-HT behavioral changes (rats) CHEM E-120

  48. GABA Agonists Prodrugs as Antipsychotics GABA reported to attenuate cognitive deficits of schizophrenia and reduce EPS from D2 antagonists. GABA does not cross BBB though. Theory - conjugate GABA with D2 antagonists that are known to cross BBB J. Med. Chem. 2008, 51, 2858 CHEM E-120

  49. GABA Agonists Prodrugs as Antipsychotics CHEM E-120

  50. GABA Agonists Prodrugs as Antipsychotics Induction of catalepsy (ip) CHEM E-120

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