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Pharmacological characteristics of ATI‐9242, a Novel Atypical Antipsychotic
Author(s) -
Choppin Agnes,
Lach Leang,
Lee Alexander,
Nunez Oscar,
Becker Cyrus,
Palme Monica P,
Paliard Xavier,
Druzgala Pascal,
Jasper Jeffrey R
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.773.12
Subject(s) - pharmacology , agonist , 5 ht receptor , receptor , chemistry , serotonin , dopamine receptor d2 , partial agonist , histamine , dopamine , intrinsic activity , atypical antipsychotic , antipsychotic , medicine , schizophrenia (object oriented programming) , biochemistry , psychiatry
ATI 9242 is a dibenzo(b,f)(1,4)oxazepine derivative designed with the goal of developing an oral drug that is effective for neuropsychiatric disorders with an improved side effect profile. The in vitro receptor profiling demonstrated that ATI 9242 has high affinity for 5‐HT 2A and D 2 receptor and submicromolar affinity for other dopamine (D 1 , D 3 , D 4 and D 5 ), serotonin (5‐HT 1A , 5‐HT 1B , 5‐HT 1D , 5‐HT 2B , 5‐HT 2C , 5‐HT 6 and 5‐HT 7 ), histamine (H 1 ) and alpha‐adrenergic (α 1B and α 2C ) receptors. In cell‐based functional assays, ATI 9242 (10 μM) had no measurable agonist activity at dopamine (D 1 , D 2S ), histamine (H 1 ), alpha‐adrenergic and serotonin (5‐HT 2A , 5‐HT 2B , 5‐HT 2C , 5‐HT 6 and 5‐HT 7 ) receptors. At the 5‐HT 1A receptor, ATI 9242 appeared to be a partial agonist (Ki=147 nM). ATI‐9242 prevented 5‐HT 2A receptor‐mediated rat aortic ring contractions in a concentration‐dependent manner (ED 50 = 3 nM), data consistent with the receptor binding results. In vivo, ATI 9242 exhibited an atypical antipsychotic‐like activity against apomorphine‐induced disruption of swimming in mice, but also in models of prepulse inhibition (PPI), without cataleptic effect (up to 30mg/kg IP), sedation (up to 10mg/kg IP), nor motor coordination impairment. Overall, the data presented herein indicate that ATI‐9242 is a novel atypical antipsychotic designed for multi‐target interactions with reduced side effects.