caa a22 4500 445377879 CHVBK 20180317143008.0 cr unu---uuuuu 170323e20111101xx s 000 0 eng 10.1007/s00702-011-0701-y doi (NATIONALLICENCE)springer-10.1007/s00702-011-0701-y II. In vitro evidence that (−)-OSU6162 and (+)-OSU6162 produce their behavioral effects through 5-HT2A serotonin and D2 dopamine receptors [Elektronische Daten] [Ethan Burstein, Maria Carlsson, Michelle Owens, Jian-Nong Ma, Hans Schiffer, Arvid Carlsson, Uli Hacksell] (−)-OSU6162 has promise for treating Parkinson's disease, Huntington's disease and schizophrenia. Behavioral tests evaluating the locomotor effects of (−) and (+)-OSU6162 on ‘low activity' animals (reserpinized mice and habituated rats) and ‘high activity' animals (drug naive mice and non-habituated rats) revealed that both enantiomers of OSU6162 had dual effects on behavior, stimulating locomotor activity in ‘low activity' animals and inhibiting locomotor activity in ‘high activity' animals. To elucidate a plausible mechanism of action for their behavioral effects, we evaluated the intrinsic actions of (−)- and (+)-OSU6162, and a collection of other antipsychotic and antiparkinsonian agents at 5-HT2A and D2 receptors in functional assays with various degrees of receptor reserve, including cellular proliferation, phosphatidyl inositol hydrolysis, GTPγS and beta-arrestin recruitment assays. We also tested for possible allosteric actions of (−)-OSU6162 at D2 receptors. Both enantiomers of OSU6162 were medium intrinsic activity partial agonists at 5-HT2A receptors and low intrinsic activity partial agonists at D2 receptors. (+)-OSU6162 had higher efficacy at 5-HT2A receptors, which correlated with its greater stimulatory activity in vivo, but (−)-OSU6162 had higher potency at D2 receptors, which correlated with its greater inhibitory activity in vivo. (−)-OSU6162 did not display any convincing allosteric properties. Both (+)- and (−)-OSU6162 were significantly less active at 27 other monoaminergic receptors and reuptake transporters tested suggesting that D2 and 5-HT2A receptors play crucial roles in mediating their behavioral effects. Compounds with balanced effects on these two receptor systems may offer promise for treating neuropsychiatric diseases. Springer-Verlag, 2011 Agonist nationallicence Partial agonist nationallicence Allosteric nationallicence Orthosteric nationallicence G-protein coupled receptor nationallicence Dopamine receptor nationallicence Serotonin receptor nationallicence Monoamine nationallicence Dopamine stabilizer nationallicence Burstein Ethan ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd, 92121, San Diego, CA, USA aut Carlsson Maria Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Box 432, 405 30, Gothenburg, Sweden aut Owens Michelle ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd, 92121, San Diego, CA, USA aut Ma Jian-Nong ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd, 92121, San Diego, CA, USA aut Schiffer Hans ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd, 92121, San Diego, CA, USA aut Carlsson Arvid Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Box 432, 405 30, Gothenburg, Sweden aut Hacksell Uli ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd, 92121, San Diego, CA, USA aut Journal of Neural Transmission Springer Vienna 118/11(2011-11-01), 1523-1533 0300-9564 118:11<1523 2011 118 702 https://doi.org/10.1007/s00702-011-0701-y text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00702-011-0701-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Burstein Ethan ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd, 92121, San Diego, CA, USA aut NATIONALLICENCE 700 1- Carlsson Maria Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Box 432, 405 30, Gothenburg, Sweden aut NATIONALLICENCE 700 1- Owens Michelle ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd, 92121, San Diego, CA, USA aut NATIONALLICENCE 700 1- Ma Jian-Nong ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd, 92121, San Diego, CA, USA aut NATIONALLICENCE 700 1- Schiffer Hans ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd, 92121, San Diego, CA, USA aut NATIONALLICENCE 700 1- Carlsson Arvid Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Box 432, 405 30, Gothenburg, Sweden aut NATIONALLICENCE 700 1- Hacksell Uli ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd, 92121, San Diego, CA, USA aut NATIONALLICENCE 773 0- Journal of Neural Transmission Springer Vienna 118/11(2011-11-01), 1523-1533 0300-9564 118:11<1523 2011 118 702 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer