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ORM-12741 for negative and cognitive symptoms of schizophrenia, depression and Alzheimer’s disease

ORM-12741 for negative and cognitive symptoms of schizophrenia, depression and Alzheimer’s disease. Juha Rouru, Ari Koivisto, Katja Kuokkanen, Jyrki Lehtimäki, Niina Jalava and Tiina Pirttilä All authors are employees of Orion Pharma.

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ORM-12741 for negative and cognitive symptoms of schizophrenia, depression and Alzheimer’s disease

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  1. ORM-12741 for negative and cognitive symptoms of schizophrenia, depression and Alzheimer’s disease Juha Rouru, Ari Koivisto, Katja Kuokkanen, Jyrki Lehtimäki, Niina Jalava and Tiina Pirttilä All authors are employees of Orion Pharma

  2. Alpha2-adrenoceptors (ARs) are G-protein coupled receptors for adrenaline and noradrenaline • Alpha2A-AR • the “major subtype” • universally expressed • mediates most of the prominent effects of non-selective alpha2-agonists and –antagonists • rodent homolog, Alpha2A/D, is pharmacologically slightly different • Alpha2B-AR • expressed mainly in the periphery but also in thalamus • mediates alpha2-agonist-evoked peripheral vasoconstriction • Alpha2C-AR • expressed mainly in the CNS (esp. striatum and hippocampus), located in GABAergic projection neurons • functional role has remained obscure, a “fine-tuner” of monoaminergic neurotransmission • modulates brain DA and 5-HT balance rather than the NA system • dopamine may also act as endogenous agonist of alpha2C-ARs

  3. Human brain autoradiography of a2C- adrenoceptors Fagerholm et al. Synapse 2008 0.8 nM [3H]RS79948-197 0.8 nM [3H]RS79948-197 + 170 nM JP-1302 54 – 64% of alpha2-binding in striatum was to to the alpha2C-subtpye

  4. Novel alpha2C-antagonists for experimental use JP-1302 ORM-10921 ORM-12741 Antagonism Kb, nM a2A: 1500 a2B: 2200 a2C: 16 a2C/2A ratio: 93 Antagonism Kb, nM a2A: 19 a2B: 5.3 a2C: 0.15 a2C/2A ratio: 130 Antagonism Kb, nM a2A: 41 a2B: 5.6 a2C: 0.01 a2C/2A ratio: 3800 Sallinen et al Brit J Pharmacology 2007 150 391-402 Sallinen et al Manuscript

  5. PRE-PULSE INHIBITION TEST: the test of choice of non-clinical CNS research to characterize antipsychotic potential of novel compounds PORSOLT’S FORCED SWIMMING TEST: screening test for characterizing antidepressant potential of novel compounds Sallinen et al Manuscript

  6. ORM-12741 and other alpha2C selective antagonists have shown beneficial effects in the following models • Sensory-motor gating (prepulse inhibition of startle reflex) (schizophrenia) • PCP induced social interaction deficit (negative symptoms of schizophrenia) • MK-801 disrupted water-maze learning (cognitive deficits of schizophrenia & Alzheimer’s disease) • Porsolt’s forced swimming test (depression) • Chronic mild stress model (depression)

  7. ORM-12741 Phase I Studies • Single ascending dose (First-in-man) study • Multiple ascending dose study • Single dose PET occupancy study • Bioavailability / food interaction study • Mass balance and characterization of main metabolites

  8. Target indications • Schizophrenia • negative symptoms • cognitive symptoms • Alzheimer’s disease • Depression

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