TY - JOUR T1 - Preclinical Characterization of Selective Phosphodiesterase 10A Inhibitors: A New Therapeutic Approach to the Treatment of Schizophrenia JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 681 LP - 690 DO - 10.1124/jpet.107.132910 VL - 325 IS - 2 AU - C. J. Schmidt AU - D. S. Chapin AU - J. Cianfrogna AU - M. L. Corman AU - M. Hajos AU - J. F. Harms AU - W. E. Hoffman AU - L. A. Lebel AU - S. A. McCarthy AU - F. R. Nelson AU - C. Proulx-LaFrance AU - M. J. Majchrzak AU - A. D. Ramirez AU - K. Schmidt AU - P. A. Seymour AU - J. A. Siuciak AU - F. D. Tingley III AU - R. D. Williams AU - P. R. Verhoest AU - F. S. Menniti Y1 - 2008/05/01 UR - http://jpet.aspetjournals.org/content/325/2/681.abstract N2 - We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug8:54–59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res985:113–126, 2003; J Histochem Cytochem54:1205–1213, 2006; Neuroscience139:597–607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology51:374–385, 2006; Neuropharmacology51:386–396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function. The American Society for Pharmacology and Experimental Therapeutics ER -