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Disorders of Mood and BehaviorSchizophrenia
Antipsychotic Drugs3/9/2011
CHEM E-120Harvard University Extension School
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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
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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) HypothesisDecrease in serotonin function, 5HT2a antagonist/inverse agonist
Clozapine Hypothesis: mixed levels of D2/5HT2/H1/M1/adrenergic activity
Glutamate Hypofunction Hypothesis: NMDA blockade, decreasedactivation of NMDA receptors
GABA Hypothesis: GABAergic system appears perturbed, lower levels of GABA reuptake sites
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Neurotransmitters - Dopamine
1/27/2010
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 cortexvery high affinity for dopaminereduced agonist induced locomotion, startle, and prepulse inhibition
D2-like decrease cAMP, open K+ channels, close Ca2+ channels
D2 caudate/putamen, NuAccknockout mice parkinsonian-like motor impairment
D3 hypothalamus
D4 frontal cortex, NuAccknockout mice hypersensitive to ethanol and stimulants
NH2HO
HO
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Neurotransmitters - Serotonin
Binds to the serotonin receptors and transporterImportant 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 drugs5-HT2C – limbic system and motor system, site of action of hallucinogenic drugs
5-HT3 - ligand-gated ion channel, 6 subtypes, stimulate adenylyl cyclase
1/27/2010
NH
HO NH2
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Antipsychotic Drugs
First generation antipsychotics (FGA) introduced 1955. Tend to be D2 antagonistsChlorpromazine (Thorazine)
Second generation antipsychotics (SGA, atypical antipsychotics)D2 antagonist/5-HT2a antagonist
HaloperidolClozapine (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
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VTAAmHYPTh
HCThalumus
Putamen NuAcc
DopamineSerotoninNorepinephrine
Cortex
Cortex
Raphe nuclei
Locus coeruleus
SchizophreniaNeurocircuitary
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SN
A9 - Substantia nigra - extrapyramidal nigrostriatal pathwayA10 – Ventral tegmental area mesolimbic pathway (positive symptoms)
mesocortical pathway (negative symptoms)
Caudate nucleus
striatum: caudate nucleus (cognition), putamen (motor), nucleus accumbens
HC - hippocampus
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Modified Dopamine HypothesisNormal State
Brainstem dopaminergic neuronsVentral tegmantal area (A10)
Limbic areastriatum
Prefrontal cortex
Mesolimbic systemMesocortical system
Negative feedbackinhibitory
Kandel p 1205
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Modified Dopamine Hypothesis - Schizophrenic State
Brainstem dopaminergic neuronsVentral tegmantal area (A10)
Limbic area (striatum)Increase in activity
Increase in dopamine levelsProduces Positive symptoms (psychosis)
Prefrontal cortexDecreased activity
Reduction in dopamine levelsD1 highly expressed
Produces Negative symptoms
Mesolimbic systemMesocortical systemdisrupted
Loss of negativefeedback
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Modified Dopamine HypothesisSchizophrenic State and EPS (side effect)
Limbic area + striatumIncrease in activity
Increase in dopamine levels, high expression levels of D2, D3, and D4
Positive symptoms
Mesolimbic systemA10
Nigrostriatal systemmotor control side effectsD2 antagonists cause EPS
EPS – extrapyramidal syndrome (involuntary movements, muscular rigidity)
VTA (A10) SN (A9)
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Serotonin - Dopamine Hypothesis - Schizophrenic State
Brainstem dopaminergic neurons
Limbic area (striatum)Increase in activity
Increase in dopamine levelsPositive symptoms
Prefrontal cortexDecreased activity
Reduction in dopamine levelsNegative symptoms
Mesolimbic systemMesocortical systemdisrupted
Raphe nuclei5-HT
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Substantia nigra (A9)
Limbic area + striatumdopamine levels
5-HT2A antagonist dec dopamine (A10)5-HT2c antagonist inc dopamine
Prefrontal cortex (dopamine)5-HT2A antagonist DA
5-HT1A agonist DA5-HT2C antagonist DA
CNS Drugs 2006, 20, 389
Raphe nuclei5-HT
Modulation of 5-HT2A, 5-HT1A, or 5-HT2C alone have no antipsychotic effectt
Serotonin - Dopamine Hypothesis - Schizophrenic State
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5-HT1A agonist (inhibit neuron, activating dopamine neurons, dec EPS)
5-HT2A antagonist (disinhibits dopaminergic neuron, increased dopamine binds to D2 preventing binding of drug antagonists,thereby dec EPS)
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Antipsychotic Drugs
First generation antipsychotics (FGA) introduced 1955. Tend to be D2 antagonistsChlorpromazine (Thorazine)
Second generation antipsychotics (SGA, atypical antipsychotics)D2 antagonist/5-HT2a antagonist
HaloperidolClozapine (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
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D2 occupancy
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
Major side-effect of FGA is extrapyramidal effects (Parkinson-type effects) due to D2 antagonism.
D2high and D2
low 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.
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First Generation Antipsychotics
Imipramine Chlorpromazine
5-HT1 pIC50 ~ 4-5 5.5
5-HT2 6.5 8
α1 5.5 5.5 (antagonist)
α2 7 (antagonist) 7.8 (antagonist)
DA 4-5 5.5 (antagonist)
D2-like 7.5 7.5
H1 7.5 (antagonist) 8
Muscarinc 7 (M2 antagonist) 7
Naunyn-Schmiedeberg’sArch Pharmacol 1984, 327, 95
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Structures of FGA/SGA Antipsychotic
FGA
D2 potency
SGA benzazepines - Similar D2 (efficacy) + 5-HT2A (efficacy/reduce EPS)
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Clozapine
Introduced in 1972Withdrawn 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
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Clozapine
Ki 5-HT2a
Ki D2
< 1.0
Receptor Ki nM Receptor Ki nM
D1 53 1 3.7
D2 36 2A 51
D3 160 2B 22
D4 22 2C 9
5-HT1A 710 H1 17
5-HT1B 1200 M1 1.9
5-HT1D 980 M2 10
5-HT2A 4 M3 14
5-HT2B 8.5 M4 18
5-HT2C 5.5
5-HT3 110
5-HT6 4
5-HT17 21
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Receptors and Effects
CNS Drugs 200822, 1047
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Newer Atypical Antipsychotics
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Atypical Antipsychotics Binding Data
MARTA – multiacting receptor-targeted antipsychotic, SDA – serotonin-dopamine antagonist
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Animal Behavioral ModelsConditioned 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 the therapeutic index for EPS.
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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 nondopaminergiccompounds 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.
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Animal Behavioral ModelsLatent 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 ofamphetamine-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.
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Animal Behavioral ModelsPrepulse 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.
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CATIE - 2005Large 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) SGAperphenazine (8 - 32 mg/day) FGAquetiapine (200 - 800 mg/day) SGArisperidone (1.5 - 6 mg/day) SGAziprasidone (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
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AripiprazoleD2 and 5-HT1A partial agonistApproved for use in USA 2002.Efficacy against positive andnegative symptoms.Same rate of EPS (21%) as placebo(19%) vs haloperidol(43%)90% bioavialable
t1/2 = 75 hours, 94 hrs active metabolite10-15 mg/daymaintenance dose 10 - 30 mg/day
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Aripiprazole
Partial agonists
Low levels of endogenous full agonist - partial agonist activeHigh levels “ - partial agonist = antagonist
In PFC will act as agonist relieving negative symptomsIn limbic/striatum will act as antagonist relieving pos symptoms
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Discovery of AripiprazoleChem. 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 haveEPS
This compound was used as a lead toexplore the development of antipsychotics with fewer side effectsNo Dopamine receptor antagonismInhibition of DA release from presynaptic neurons or inhibit DA synthesis
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Discovery of AripiprazoleChem. 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 mice1. 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
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Discovery of Aripiprazole
Inhibition of jumping behavior
5>6,7>8
No -adrenergic antagonism (side effects)
8>7>>6>5
Inhibition of jumping behavior
n = 3 ≥ 4 >> 2,5
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Discovery of Aripiprazole
Inhibition of jumping behavior
1-2 substituents found to enhance activity2,3-dichloro reduced activity ED50 37 mg/kg2-CH3 ED50 0.7 mg/kg2,3-diCH3 ED50 1.2 mg/kg2-F ED50 1.9 mg/kg
Induction of catalepsy in mice < chlorpromazine and haloperidol
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Discovery of Aripiprazole
Was in clinical trials but stoppedAggravated positive symptomsIn some patients
AutoreceptorAgonisteffects
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Discovery of Aripiprazole
J Med Chem 1998, 41, 658
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)
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Discovery of Aripiprazole ED50 mol/kg po (anti-APO test)41
26
17
2.8
>23
Butoxy chain best
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Discovery of Aripiprazole
Anti-APO testED50 mol/kg po
If 2 = CH3, at 3 Cl = Br >FIf 2 = CH3, electron-withdrawing at 3 increases potency
electron-releasing at 3 decreases potency2-CH3,3-Cl ED50 = 2.8 mol/kg po2-Cl, 3-CH3 ED50 = 0.9 mol/kg po
2,3-(Cl)2 ED50 = 0.6 mol/kg po2,4 >7.02,5 2.72,6 >7.03,4 >7.03,5 1.1
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Discovery of Aripiprazole
Anti-APO testPosition ED50 mol/kg po5 >226 >227 0.68 >22
SAR results for Postsynaptic DA receptor antagonism
Side chain C4 > C3 and C5
1-2 substituents on aromatic ring2-OCH2CH3 best for 1 substituent2,3-dichloro best for 2 substituentsSubstitution at position 7 of 3,4-dihydroquinolinone ring is best
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Discovery of Aripiprazole
measurement of peripheral activity
ED50 mol/kg po
Inhibit GBLInduced DOPAsynthesis
B/A
adverse effectbeneficial effect
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Discovery of Aripiprazole Time course of inhibition of APO-induced sterotypyat 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 hoursED50 11.8 mol/kg
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Discovery of Aripiprazole
Agonist activity
Antagonistactivity
JPET 1995, 274, 329
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Metabolism of Aripiprazole
Ki (nM)Receptor Aripiprazole OPC-14857
5-HT2A 7.9 2.55-HT2C 126 63D2 1 0.5D3 10 205-HT6 100 79
European J Pharmacology 2006, 546, 88
OPC-14857Aripiprazole
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Metabolism of Aripiprazole
Full agonist
EC50 4.7 nM
EC50 1.5 nM
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Bifeprunox (DU-127090) - Solvay
D2 Ki = 3.2 nM partial agonist (28% at 1M)5-HT1A Ki = 10 nM partial agonist, D3 Ki = 0.6 nMD4 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
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D2 antagonist/5-HT1A agonist
Tried to mimic (bioisostere)Biphenyl methylaminebut could notBiphenyl critical
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D2 antagonist/5-HT1A agonist
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D2 antagonist/5-HT1A agonist
16 20
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D2 antagonist/5-HT1A agonist
Inhibition ofmethyl phenidate(indirect DA agonist)induced stereotypy& hyperlocomotion
Potency to inducecatalepsy
Lower lipretraction5-HT1A agonist
Flat-bodysyndrome
1.1 - 8.3 mg/kg - range of 5-HT1A agonism to achieve antipsychotic effects w/o negative 5-HT behavioral changes (rats)
5-HT1A/D2
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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
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GABA Agonists Prodrugs as Antipsychotics
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GABA Agonists Prodrugs as Antipsychotics
Induction of catalepsy (ip)
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GABA Agonists Prodrugs as Antipsychotics
Prolactin inc as measure of D antagonism (ip)
Plasma prolactin levels inrats treated poPerphenazine 5, 10, 20 mg/kg3 7,14,28 mg/kg
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GABA Agonists Prodrugs as Antipsychotics
Perphenazine and 3 · 3HCl abrogate hyperactivity induced by D-amphetamine in rats. Male Wistar rats divided into five groups (six/group) were treated po respectively with: vehicle (1% lactic acid, two groups); perphenazine (2.5 mg/kg); an equimolar dose of 3 · 3HCl;and GABA (1 mg/kg). With the exception of one of the vehicle treatedgroups, which served as negative control, after 90 min all other animalsreceived D-amphetamine (2.0 mg/kg, ip). The rats were then placedindividually in barrels, and the number of head movements and climbingattempts on the barrel walls were recorded double-blindly.
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Emerging Targets
Muscarinc M1/M4 agonist - antipsychotic activity w/o catalepsy
7 nAChR (nicotinic acetylcholine) partial agonistCognition enhancing propertiesHighly expressed in PFC, perhaps involved in sensory gating
JMC 2006, 49, 4374
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Emerging Targets
Histamine H3 Antagonists - potential for cognitive improvementGluamatergic - NMDA positive allosteric modulationMetabotropic Glutamate (mGLUR) agonist
mGlu2/3 agonists - Phase 2 trial (Nature Medicine 2007, 13, 1102)AMPA agonistGlutamate transporter inhibitionD4 antagonistsPhosphodiesterase inhibitors - PDE4Neurokinin - NK3 antagonists (Bioorganic & Med. Chem Lett 2009, 19, 837)Cannabinoids - CB1 antagonists can reduce stimulant-induced hyperactivity
J. Medicinal Chemistry 2008, 51, 1077-1107 Emerging Opportunities for Antipsychotic Drug Discovery in the Postgenomic EraPharmacological Reviews 2008, 60, 358-403, Antipsychotic Drugs: Comparison inAnimal Models of Efficacy, Neurotransmitter Regulation, and Neuroprotection.
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