Ratherthan directly activating the D1R, a PAM will potentiatethe action of endogenous DA, thus inducing a more physiological modeof action and avoiding the pitfalls displayed by orthosteric ligandssuch as overstimulation, tolerance development, and low tolerability.11,37 However, this therapeutic potential has not been clinically assessedfor disclosed D1R PAMs.11 Amongthem, LY3154207 and ASP4345 (Figure 1) have reached phase 2 development for the treatmentof PD and schizophrenia, respectively, which will hopefully validatethe clinical use of a D1R PAM.38−40. This evidence concerns the gene DRD1 and schizophrenia.