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Cristina Fernández-Fernández,1 Luis F Callado,2 Rocío Girón,3 Eva Sánchez,3 Amaia M Erdozain,2 José Antonio López-Moreno,4 Paula Morales,1 Fernando Rodríguez de Fonseca,5 Javier Fernández-Ruiz,6 Pilar Goya,1 J Javier Meana,2 M Isabel Martín,3 Nadine Jagerovic1 1Instituto de Química Médica, CSIC, Madrid, 2Departamento de Farmacología, Universidad del Pais Vasco, UPV/EHU, CIBERSAM, Leioa, 3Departamento de Farmacología y Nutrición, Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, 4Departamento de Psicobiologia, Universidad Complutense de Madrid, Madrid, 5Laboratorio de Medicina Regenerativa, Hospital Carlos Haya, Fundación IMABIS, Málaga, 6Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, CIBERNED, IRYCIS, Universidad Complutense de Madrid, Madrid, Spain Abstract: 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 [35S]-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. Keywords: fentanyl, rimonabant, cannabinoid, opioid, behavioral assays