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

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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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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


n = 3 ≥ 4 >> 2,5

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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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Was in clinical trials but stoppedAggravated positive symptomsIn some patients

AutoreceptorAgonisteffects

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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

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17

2.8

>23

Butoxy chain best

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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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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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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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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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16 20

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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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Induction of catalepsy (ip)

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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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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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