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 Muscarinc M1/M4 agonist - antipsychotic activity w/o catalepsy was in Phase 3 for Alzheimers but withdrawn (M3 mediated side effects of salivation, diarrhea, sweating).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

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Xanomeline M1/M4 agonist

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M1/M4 agonist Muscarinc M1/M4 agonist - antipsychotic activity w/o catalepsy was in Phase 3 for Alzheimers but withdrawn (M3 mediated side effects of salivation, diarrhea, sweating) CHEM E-120

  2. Xanomeline M1/M4 agonist British J. Pharmacology 1998, 1413 Aripiprazole 5-HT1A partial agonist agonist FGA antipsychotics antagonists antagonist CHEM E-120

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

  4. 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

  5. SGA benzazepines - Similar D2 (efficacy) + 5-HT2A (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, 4374 CHEM E-120

  7. 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

  8. 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

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