Morphine is an alkaloid from the opium poppy used to treat pain. The potentially lethal side effects of morphine and related opioids-which include fatal respiratory depression-are thought to be mediated by mu-opioid-receptor (mu OR) signalling through the beta-arrestin pathway or by actions at other receptors. Conversely, G-protein mu OR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the mu OR structure and identify new scaffolds unrelated to known opioids. Structure-based optimization yields PZM21-a potent G(i) activator with exceptional selectivity for mu OR and minimal beta-arrestin-2 recruitment. Unlike morphine, PZM21 is more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses. PZM21 thus serves as both a probe to disentangle mu OR signalling and a therapeutic lead that is devoid of many of the side effects of current opioids.