Opiates such as morphine are the choice analgesic in the treatment of chronic pain due to their potent and rapid action. Opioid receptors belong to the family of G protein-coupled receptors (GPCRs), one of the largest gene families in the mammalian genome. The OPRM1 gene encodes the mu opioid receptor, which is the primary site of action for morphine and other commonly used opioids such as heroin, fentanyl, and methadone. The long-term use of opiates is limited because of the development of tolerance and dependence, as well as respiratory suppression and constipation. Due to their clinical importance, various strategies have been considered for making opiates more effective while curbing liabilities such as addiction. One such strategy has been to use a combination of drugs to improve the effectiveness of morphine. In particular, delta opioid receptor (OPRD1) ligands have been useful in enhancing morphine’s potency, but the underlying molecular basis is not understood. It has been shown that modulation of receptor function by physical association between OPRM1 and OPRD1 is a potential mechanism; heteromerization of OPRM1 with OPRD1 leads to the modulation of receptor binding and signaling properties. It has further been shown that the selective activation of the OPRM1-OPRD1 heteromer by a combination of OPRM1 agonist with OPRD1 antagonist can be blocked by antibodies that selectively recognize the heteromer. Therefore, the identification of compounds that selectively activate OPRM1-OPRD1 heterodimerization may have potential in the treatment of pain and alleviate unwanted effects associated with opiate use. The Scripps Research Institute Molecular Screening Center (SRIMSC), part of the Molecular Libraries Probe Production Centers Network (MLPCN), reports here an agonist for OPRM1-OPRD1 heterdimerization, ML335, with an EC50 of 403 nM, and selectivities vs. OPRM1, OPRD1, and HTR5A of 37, 2.7, and >99, respectively.