ABT‐127, a novel Dopamine D3 Receptor Antagonist: Cardiovascular Profile in the Anesthetized Dog

Abstract

ABT-127 is a novel and orally efficacious dopamine D3-selective antagonist targeted for the treatment of schizophrenia (pre-clinical efficacious Cmax 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 Cmax) 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/dtmax at concentrations as high as 1.29 μg/mL (26-fold); at higher concentrations (2.67 to 3.36 μg/mL) dP/dtmax 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 Cmax). 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 Cmax).