Based on numerous pharmacological studies that have revealed an interaction between cannabinoid and opioid systems at the molecular, neurochemical, and behavioral levels, a new series of hybrid molecules has been prepared by coupling the molecular features of two wellknown drugs, ie, rimonabant and fentanyl. The new compounds have been tested for their affinity and functionality regarding CB1 and CB2 cannabinoid and μ opioid receptors. In [(35)S]-GTPγS (guanosine 5'-O-[gamma-thio]triphosphate) binding assays from the post-mortem human frontal cortex, they proved to be CB1 cannabinoid antagonists and μ opioid antagonists. Interestingly, in vivo, the new compounds exhibited a significant dual antagonist action on the endocannabinoid and opioid systems. ; Journal Article; Research Support, Non-U.S. Gov't; This work was supported by grants from the Spanish Ministry of Economy and Competitivity (SAF2012-40075, SAF2009-12422, SAF2010-20521, SAF2011-26818), Red de Trastornos Adictivos (RETICS RD06/001), the Madrid Gov¬ernment (CANNAB-CM, S2010/BMD-2308), the University of the Basque Country (UFI 11/35), the Basque Government (IT-199-07, SAIOTEK S-PE10UN14), and the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM. AME is the recipient of a pre¬doctoral fellowship from the Basque Government. PM is the recipient of a fellowship (JAE-Pre-2010-01119) from Junta para la Ampliación de Estudios, cofinanced by the European Social Fund.