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M1/M4 agonist Muscarinc M1/M4 agonist - antipsychotic activity w/o catalepsy was in Phase 3 for Alzheimers but withdrawn (M3 mediated side effects of salivation, diarrhea, sweating) 3/9/11CHEM E-120

2. 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

3. 33/9/11CHEM E-120 Xanomeline M1/M4 agonist PPI reduces startle inhibition of PPI potentiates startle

4. Lurasidone (Latuda) - Approved by FDA for schizophrenia in 2010 AntagonistK i (nM)AgonistK i (nM) D21 5-HT 1A 6.7 5HT 2A 0.5 5-HT 7 0.5 α 2C 11 European Journal of Pharmacology 2007, 572 (2-3): 160–70 Lurasidone

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

6. 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, 4374 3/9/11CHEM E-120

7. 7  7 nAChR (nicotinic acetylcholine) 3/9/11CHEM E-120 Pfizer J Med. Chem. 2010 Sanofi-Aventis Neuropsychopharm 2007 SSR180711 Targacept & AstraZeneca Phase 2  7 K 1 = 1 nM

8. 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, 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. 3/9/11CHEM E-120