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P0279 - RGH-188, a d3/d2 dopamine receptor antagonist/partial agonist atypical antipsychotic candidate
- I. Laszlovszky, B. Kiss, I. Gyertyan, G. Pasztor Meszaros, N. Seneca, E. Schmidt, Z.S. Nemethy, G.Y. Bugovics, K. Saghy, J. Laszy, M. Kapas, G.Y. Nemeth, Z.S. Szombathelyi
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- Journal:
- European Psychiatry / Volume 23 / Issue S2 / April 2008
- Published online by Cambridge University Press:
- 16 April 2020, p. S163
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- Article
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Objectives:
RGH-188 is an orally active, potent dopamine D3/D2 receptor antagonist/partial agonist atypical antipsychotic for the treatment of schizophrenia and bipolar mania.
Results:RGH-188 displayed high affinity to human D3 receptors (Ki: 0.085 nM) and approximately six- and thirty-times less affinity to human D2, and 5-HT1A receptors. In various in vitro and in vivo assays RGH-188 behaved either as an antagonist or as a partial agonist on dopamine D3 and D2 receptors.
RGH-188 displayed potent antipsychotic activity (0.1-0.8 mg/kg) in rodent models such as apomorphine-induced climbing, amphetamine- and phencyclidine-induced hypermotility, conditioned avoidance response. It significantly improved the learning performance of rats (0.02-0.2 mg/kg) impaired by scopolamine in a water-labyrinth learning paradigm. RGH-188 showed no EPS liability as it produced no catalepsy up to 100-fold therapeutic range.
In a nonhuman primate positron emission tomography (PET) study using 11C-raclopride RGH-188 occupied striatal D2/D3 receptors in a dose dependent and saturable manner with an ED50 of 7 μg/kg iv. In healthy male subjects multiple administration of 1 mg RGH-188 resulted in over 70% D2/D3 receptor occupancy and the displacement showed correlation with RGH-188 and metabolites plasma levels.
After single administration to healthy volunteers, Tmax for RGH-188 was 3-4 hours and the terminal disposition half-life was 5-6 days. Over the dose range of 0.5-2.5 mg AUC of the parent drug was approximately dose-proportional. Systemic exposure to the pharmacologically active metabolites, desmethyl- and didesmethyl-RGH-188 was 20-30% and 50-200% of that to the parent, respectively.
Contributors
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- By Shamsuddin Akhtar, Greg Albert, Sidney Allison, Muhammad Anwar, Haruo Arita, Amanda Barker, Mary Hanna Bekhit, Jeanna Blitz, Tyson Bolinske, David Burbulys, Asokumar Buvanendran, Gregory Cain, Keith A. Candiotti, Daniel B. Carr, Derek Chalmers, John Charney, Rex Cheng, Roger Chou, Keun Sam Chung, Anna Clebone, Frederick Conlin, Susan Dabu-Bondoc, Tiffany Denepitiya-Balicki, Jeanette Derdemezi, Anahat Kaur Dhillon, Ho Dzung, Juan Jose Egas, Stephen M. Eskaros, Zhuang T. Fang, Claudia R. Fernandez Robles, Victor A. Filadora, Ellen Flanagan, Dan Froicu, Allison Gandey, Nehal Gatha, Boris Gelman, Christopher Gharibo, Muhammad K. Ghori, Brian Ginsberg, Michael E. Goldberg, Jeff Gudin, Thomas Halaszynski, Martin Hale, Dorothea Hall, Craig T. Hartrick, Justin Hata, Lars E. Helgeson, Joe C. Hong, Richard W. Hong, Balazs Horvath, Eric S. Hsu, Gabriel Jacobs, Jonathan S. Jahr, Rongjie Jaing, Inderjeet Singh Julka, Zeev N. Kain, Clinton Kakazu, Kianusch Kiai, Mary Keyes, Michael M. Kim, Peter G. Lacouture, Ryan Lanier, Vivian K. Lee, Mark J. Lema, Oscar A. de Leon-Casasola, Imanuel Lerman, Philip Levin, Steven Levin, JinLei Li, Eric C. Lin, Sharon Lin, David A. Lindley, Ana M. Lobo, Marisa Lomanto, Mirjana Lovrincevic, Brenda C. McClain, Tariq Malik, Jure Marijic, Joseph Marino, Laura Mechtler, Alan Miller, Carly Miller, Amit Mirchandani, Sukanya Mitra, Fleurise Montecillo, James M. Moore, Debra E. Morrison, Philip F. Morway, Carsten Nadjat-Haiem, Hamid Nourmand, Dana Oprea, Sunil J. Panchal, Edward J. Park, Kathleen Ji Park, Kellie Park, Parisa Partownavid, Akta Patel, Bijal Patel, Komal D. Patel, Neesa Patel, Swati Patel, Paul M. Peloso, Danielle Perret, Anthony DePlato, Marjorie Podraza Stiegler, Despina Psillides, Mamatha Punjala, Johan Raeder, Siamak Rahman, Aziz M. Razzuk, Maggy G. Riad, Kristin L. Richards, R. Todd Rinnier, Ian W. Rodger, Joseph Rosa, Abraham Rosenbaum, Alireza Sadoughi, Veena Salgar, Leslie Schechter, Michael Seneca, Yasser F. Shaheen, James H. Shull, Elizabeth Sinatra, Raymond S. Sinatra, Neil Singla, Neil Sinha, Denis V. Snegovskikh, Dmitri Souzdalnitski, Julie Sramcik, Zoreh Steffens, Alexander Timchenko, Vadim Tokhner, Marc C. Torjman, Co T. Truong, Nalini Vadivelu, Ashley Vaughn, Anjali Vira, Eugene R. Viscusi, Dajie Wang, Shu-ming Wang, J. Michael Watkins-Pitchford, Steven J. Weisman, Ira Whitten, Bryan S. Williams, Jeremy M. Wong, Thomas Wong, Christopher Wray, Yaw Wu, Anthony T. Yarussi, Laurie Yonemoto, Bita H. Zadeh, Jill Zafar, Martha Zegarra, Keren Ziv
- Edited by Raymond S. Sinatra, Jonathan S. Jahr, University of California, Los Angeles, School of Medicine, J. Michael Watkins-Pitchford
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- Book:
- The Essence of Analgesia and Analgesics
- Published online:
- 06 December 2010
- Print publication:
- 14 October 2010, pp xi-xviii
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