In this study, we investigated the cardioprotective effects of novel tetrahydroisoquinoline nitrobenzylmercaptopurine riboside (NBMPR) analogue NT inhibitors, Compound 2 and Compound 4 in isolated perfused rat hearts. Langendorff-perfused heart preparations were subjected to 10 min compound or vehicle control treatment, followed by 30 min global ischemia, and then 120 min reperfusion. For infarct size determination, reperfusion time was 180 min. At 1 µM, both compounds provided excellent cardioprotection, with left ventricular developed pressure (LVDP) recovery and end diastolic pressure (EDP) increase of 82.9 ± 4.0% (p<0.001) and 14.1 ± 2.0 mmHg (p<0.03), respectively, for Compound 2-treated hearts, and 79.2 ± 5.9% (p<0.002) and 7.5 ± 2.7 mmHg (p<0.01), respectively for Compound 4-treated hearts, compared to control values of 41.6 ± 5.2% and 42.5 ± 6.5 mmHg, respectively. LVDP recovery and EDP rise for NBMPR-treated hearts at the 1 µM dose level were 64.1 ± 4.2% and 29.1 ± 2.5 mmHg, respectively. Compound 4 was the best cardioprotective agent, affording significant cardioprotection even at the lower dose of 0.1 µM, with LVDP recovery and EDP rise values of 76.0 ± 4.9% (p<0.003) and 14.1 ± 1.0 mmHg (p<0.03), respectively. At 1 µM, Compound 4 and NBMPR reduced infarct size with infarct area to total risk area ratios (I/R) of 29.13 ± 3.17, p<0.001 for Compound 4, and 37.5 ± 3.42 (p<0.01) for NBMPR vs. control value of 51.08 ± 5.06 %. Compound 4 was more effective than NBMPR in infarct size reduction (p<0.02). These new tetrahydroisoquinoline NBMPR analogues are not only potent cardioprotective agents, but they are also better than NBMPR in this model.