CCK is known to give an anti-opioid effect and as a result, causes an increase of pain by inhibiting the opioid response. Recent research has shown further that melancortin receptors, mainly subtype MC4R, produce an increase in response to pain stimuli. Based on these observations, we are developing multimeric ligands which will be of benefit to therapeutic pain treatment with enhanced opioid efficacy by acting as agonists at opioid receptors and antagonists at both CCK and melanocortin receptors. The design of the ligands was based on the hypothesis of targeting multiple receptors with overlapping pharmacophores. CCK (I) and melanocortin (II) pharmacophores were overlapped by Trp, and opioid pharmacophores (III) were linked to the N-terminal of the melanocortin pharmacophore (Figure). The designed ligands showed moderate to high biological activity at all three receptors depending on their respective structures. Design considerations and structure-activity relationships will be discussed in detail along with in-vivo assay results. This work was supported by grants from National Institute on Drug Abuse (DA12394 and DA06284).