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Xanomeline M1/M4 agonist. Muscarinc M1/M4 agonist - antipsychotic activity w/o catalepsy was in Phase 3 for Alzheimers but withdrawn (M3 mediated side effects of salivation, diarrhea, sweating). Xanomeline M1/M4 agonist. British J. Pharmacology 1998, 1413.

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xanomeline m1 m4 agonist
Xanomeline M1/M4 agonist

Muscarinc M1/M4 agonist - antipsychotic activity w/o catalepsy

was in Phase 3 for Alzheimers but withdrawn (M3 mediated side effects

of salivation, diarrhea, sweating)

CHEM E-120

slide2

Xanomeline M1/M4 agonist

British J. Pharmacology 1998, 1413

Aripiprazole 5-HT1A partial agonist

agonist

FGA antipsychotics antagonists

antagonist

CHEM E-120

slide3

Xanomeline M1/M4 agonist

PPI reduces startle

inhibition of PPI potentiates

startle

CHEM E-120

slide4

Lurasidone

Lurasidone (Latuda) - Approved by FDA for schizophrenia in 2010

Antagonist Ki (nM) Agonist Ki (nM)

D2 1 5-HT1A 6.7

5HT2A 0.5

5-HT7 0.5

α2C 11

European Journal of Pharmacology 2007, 572 (2-3): 160–70

7 nachr nicotinic acetylcholine
7 nAChR (nicotinic acetylcholine)

7 nAChR (nicotinic acetylcholine) partial agonist

Cognition enhancing properties

Highly expressed in PFC, perhaps involved in sensory gating

JMC 2006, 49, 4374

CHEM E-120

7 nachr nicotinic acetylcholine7
7 nAChR (nicotinic acetylcholine)

Sanofi-Aventis Neuropsychopharm 2007

SSR180711

Pfizer J Med. Chem. 2010

Targacept & AstraZeneca Phase 2

7 K1 = 1 nM

CHEM E-120

emerging targets
Emerging Targets

Histamine H3 Antagonists - potential for cognitive improvement

Gluamatergic - NMDA positive allosteric modulation

Metabotropic Glutamate (mGLUR) agonist

mGlu2/3 agonists - Phase 2 trial (Nature Medicine 2007, 13, 1102)

AMPA agonist

Glutamate transporter inhibition

D4 antagonists

Phosphodiesterase inhibitors - PDE4

PDE10 partnership Pfizer/Biotie 2010

Neurokinin - 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 Era

Pharmacological Reviews 2008, 60, 358-403, Antipsychotic Drugs: Comparison in

Animal Models of Efficacy, Neurotransmitter Regulation, and Neuroprotection.

CHEM E-120