CNR1 and obesity due to melanocortin 4 receptor deficiency: Thus, aiming at avoidance of undesired psychotropic side effects, blood-brain-barrier impermeable CB1 inverse agonists, such as JD5037 or TM38837 and global neutral antagonists that are brain penetrant, such as AM4113 were developed as second generation CB1-dependent pharmaceuticals, and so far have been successfully tested in rodent models of obesity and metabolic syndrome [403].