1 Xanomeline M1/M4 agonist Muscarinc M1/M4 agonist - antipsychotic activity w/o catalepsy was in Phase 3 for Alzheimers but withdrawn (M3 mediated side.

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1 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M1/M4 agonist Muscarinc M1/M4 agonist - antipsychotic activity w/o catalepsy was in Phase 3 for Alzheimers but withdrawn (M3 mediated side effects of salivation, diarrhea, sweating) 3/9/11CHEM E-120

23/9/11CHEM E-120 Xanomeline M1/M4 agonist British J. Pharmacology 1998, 1413 agonist antagonist Aripiprazole 5-HT 1A partial agonist FGA antipsychotics antagonists

33/9/11CHEM E-120 Xanomeline M1/M4 agonist PPI reduces startle inhibition of PPI potentiates startle

Lurasidone (Latuda) - Approved by FDA for schizophrenia in 2010 AntagonistK i (nM)AgonistK i (nM) D21 5-HT 1A 6.7 5HT 2A HT α 2C 11 European Journal of Pharmacology 2007, 572 (2-3): 160–70 Lurasidone

SGA benzazepines - Similar D 2 (efficacy) + 5-HT 2A (efficacy/reduce EPS) 1 2 3

6  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, /9/11CHEM E-120

7  7 nAChR (nicotinic acetylcholine) 3/9/11CHEM E-120 Pfizer J Med. Chem Sanofi-Aventis Neuropsychopharm 2007 SSR Targacept & AstraZeneca Phase 2  7 K 1 = 1 nM

8 Emerging Targets Histamine H 3 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 D 4 antagonists Phosphodiesterase inhibitors - PDE4 PDE10 partnership Pfizer/Biotie 2010 Neurokinin - NK 3 antagonists (Bioorganic & Med. Chem Lett 2009, 19, 837) Cannabinoids - CB 1 antagonists can reduce stimulant-induced hyperactivity J. Medicinal Chemistry 2008, 51, Emerging Opportunities for Antipsychotic Drug Discovery in the Postgenomic Era Pharmacological Reviews 2008, 60, , Antipsychotic Drugs: Comparison in Animal Models of Efficacy, Neurotransmitter Regulation, and Neuroprotection. 3/9/11CHEM E-120