March 6th, 2009ASENT meeting / Juha RouruOrion Group Orion Pharma 1 ORM 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

March 6th, 2009ASENT meeting / Juha RouruOrion Group Orion Pharma 2 Alpha 2A -AR –the “major subtype” –universally expressed –mediates most of the prominent effects of non-selective alpha 2 - agonists and –antagonists –rodent homolog, Alpha 2A/D, is pharmacologically slightly different Alpha 2B -AR –expressed mainly in the periphery but also in thalamus –mediates alpha2-agonist- evoked peripheral vasoconstriction Alpha 2C -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 alpha 2C -ARs Alpha 2 -adrenoceptors (ARs) are G-protein coupled receptors for adrenaline and noradrenaline

March 6th, 2009ASENT meeting / Juha RouruOrion Group Orion Pharma 3 Human brain autoradiography of  2C - adrenoceptors 54 – 64% of alpha2-binding in striatum was to to the alpha2C-subtpye 0.8 nM [ 3 H]RS nM [ 3 H]RS nM JP-1302 Fagerholm et al. Synapse 2008

March 6th, 2009ASENT meeting / Juha RouruOrion Group Orion Pharma 4 Novel alpha2C-antagonists for experimental use Antagonism Kb, nM  2A : 1500  2B : 2200  2C : 16  2C/2A ratio: 93 JP-1302ORM Sallinen et al Brit J Pharmacology Sallinen et al Manuscript Antagonism Kb, nM  2A : 19  2B : 5.3  2C : 0.15  2C/2A ratio: 130 ORM Antagonism Kb, nM  2A : 41  2B : 5.6  2C : 0.01  2C/2A ratio: 3800

March 6th, 2009ASENT meeting / Juha RouruOrion Group Orion Pharma 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

March 6th, 2009ASENT meeting / Juha RouruOrion Group Orion Pharma 6 ORM 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)

March 6th, 2009ASENT meeting / Juha RouruOrion Group Orion Pharma 7 ORM 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

March 6th, 2009ASENT meeting / Juha RouruOrion Group Orion Pharma 8 Target indications Schizophrenia –negative symptoms –cognitive symptoms Alzheimer’s disease Depression