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ABT‐127, a novel Dopamine D3 Receptor Antagonist: Cardiovascular Profile in the Anesthetized Dog
Author(s) -
Fryer Ryan M,
Preusser Lee C,
Xu Hongyu,
Marsh Kennan C,
Cox Bryan F,
Haupt Andreas,
Schoemaker Hans,
Sullivan James P,
Drescher Karla U,
Reinhart Glenn A
Publication year - 2006
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.20.5.a1109-b
Subject(s) - beagle , cmax , hemodynamics , pentobarbital , heart rate , antagonist , qt interval , pharmacology , medicine , blood pressure , anesthesia , dopamine receptor d3 , dopamine , chemistry , dopamine receptor , pharmacokinetics , receptor
ABT‐127 is a novel and orally efficacious dopamine D 3 ‐selective antagonist targeted for the treatment of schizophrenia (pre‐clinical efficacious C max in a rat model of social interaction = 50 ng/mL) and is hypothesized to produce fewer cardiovascular effects than classical or atypical antipsychotics that target multiple receptors. Thus, the cardiovascular profile of ABT‐127 was delineated during three 30‐min escalating infusions in the pentobarbital anesthetized beagle dog. In low‐ and high‐dose studies (n=6–8/group) ABT‐127 produced only a modest increase in heart rate (9 ± 3%) at 2.67 μg/mL (53‐fold the C max ) and produced no effect on blood pressure, cardiac output, or systemic vascular resistance at the highest concentrations tested (3.36 μg/mL; 67‐fold). Moreover, ABT‐127 produced no effect on left ventricular dP/dt max at concentrations as high as 1.29 μg/mL (26‐fold); at higher concentrations (2.67 to 3.36 μg/mL) dP/dt max fell to −13 ± 3 and −21 ± 2% below baseline. ABT‐127 produced no increase in the QT‐interval corrected for changes in heart rate (QTc) at any concentration tested (up to 3.36 μg/mL; 67‐fold the C max ). In contrast, both classical and atypical antipsychotics have been shown to produce dose‐dependent hemodynamic and electrocardiographic effects (increases in QTc) in the same model and in patients. These data suggest that ABT‐127 has a relatively benign cardiovascular profile and produces no increases in QTc and only modest hemodynamic effects at the highest concentration tested (3.36 μg/mL or 67‐fold the pre‐clinical efficacious C max ).