The treatment of pain by opioids is limited by common adverse side effects, including addiction, constipation, and respiratory depression. Efforts have been dedicated to the discovery of improved opioids, including opioid receptor partial agonists. We have developed functionally selective ligands that are devoid of these side effects. Furthermore, other approaches are focused on analgesics that target non–opioid-sensitive links in the pain processing circuitry. The G protein-coupled serotonin receptor 5-HT1AR mediates antinociception and may serve as a valuable target for the treatment of pain. Starting from a chemical library, ST171, a bitopic chemotype activating 5-HT1AR was evolved. In vitro pharmacological investigations of ST171 revealed potent and selective Gi activation), with marginal Gs and β-arrestin recruitment. Preclinical studies in mice showed that ST171 was effective in acute and chronic pain models, without causing sedation. Comparison of cryo-EM structures of a 5-HT1AR-Gi complex bound to the functionally biased agonist ST171, with a structure bound to the functionally balanced agonist befiradol, showed that both ligands bind to the same orthosteric site, but address different exo-sites. The seminar will show our very recent developments in the design, synthesis and biological investigation of GPCR ligands that may be helpful for the development of opioid or non-opioid analgesic drugs.