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      Is Open Access

      Combining rimonabant and fentanyl in a single entity: preparation and pharmacological results

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          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 CB 1 and CB 2 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 CB 1 cannabinoid antagonists and μ opioid antagonists. Interestingly, in vivo, the new compounds exhibited a significant dual antagonist action on the endocannabinoid and opioid systems.

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          Most cited references 35

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          Prediction of drug solubility from structure.

          The aqueous solubility of a drug is an important factor affecting its bioavailability. Numerous computational methods have been developed for the prediction of aqueous solubility from a compound's structure. A review is provided of the methodology and quality of results for the most useful procedures including the model implemented in the QikProp program. Viable methods now exist for predictions with less than 1 log unit uncertainty, which is adequate for prescreening synthetic candidates or design of combinatorial libraries. Further progress with predictive methods would require an experimental database of highly accurate solubilities for a large, diverse collection of drug-like molecules.
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            Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal.

            Withdrawal from opiates, such as heroin or oral narcotics, is characterized by a host of aversive physical and emotional symptoms. High rates of relapse and limited treatment success rates for opiate addiction have prompted a search for new approaches. For many opiate addicts, achieving abstinence may be further complicated by poly-drug use and co-morbid mental disorders. Research over the past decade has shed light on the influence of endocannabinoids (ECs) on the opioid system. Evidence from both animal and clinical studies point toward an interaction between these two systems, and suggest that targeting the EC system may provide novel interventions for managing opiate dependence and withdrawal. This review will summarize the literature surrounding the molecular effects of cannabinoids and opioids on the locus coeruleus-norepinephrine system, a key circuit implicated in the negative sequelae of opiate addiction. A consideration of the trends and effects of marijuana use in those seeking treatment to abstain from opiates in the clinical setting will also be presented. In summary, the present review details how cannabinoid-opioid interactions may inform novel interventions in the management of opiate dependence and withdrawal. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.
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              Advances in the field of cannabinoid--opioid cross-talk.

              A remarkable amount of literature has been generated demonstrating the functional similarities between the endogenous opioid and cannabinoid systems. Anatomical, biochemical and molecular data support the existence of reciprocal interactions between these two systems related to several pharmacological responses including reward, cognitive effects, and the development of tolerance and dependence. However, the assessment of the bidirectionality of these effects has been difficult due to their variety and complexity. Reciprocal interactions have been well established for the development of physical dependence. Cross-tolerance and cross-sensitization, although not always bidirectional, are also supported by a number of evidence, while less data have been gathered regarding the relationship of these systems in cognition and emotion. Nevertheless, the most recent advances in cannabinoid-opioid cross-modulation have been made in the area of drug craving and relapse processes. The present review is focused on the latest developments in the cannabinoid-opioid cross-modulation of their behavioural effects and the possible neurobiological substrates involved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2014
                20 February 2014
                : 8
                : 263-277
                Affiliations
                [1 ]Instituto de Química Médica, CSIC, Madrid, Spain
                [2 ]Departamento de Farmacología, Universidad del Pais Vasco, UPV/EHU, CIBERSAM, Leioa, Spain
                [3 ]Departamento de Farmacología y Nutrición, Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain
                [4 ]Departamento de Psicobiologia, Universidad Complutense de Madrid, Madrid, Spain
                [5 ]Laboratorio de Medicina Regenerativa, Hospital Carlos Haya, Fundación IMABIS, Málaga, Spain
                [6 ]Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, CIBERNED, IRYCIS, Universidad Complutense de Madrid, Madrid, Spain
                Author notes
                Correspondence: Nadine Jagerovic, Instituto de Química Médica, CSIC, C/Juan de la Cierva 3, E-28006 Madrid, Spain, Tel +34 9 1562 2900, Fax +34 9 1564 4853, Email nadine@ 123456iqm.csic.es
                Article
                dddt-8-263
                10.2147/DDDT.S55045
                3934591
                © 2014 Fernández-Fernández et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                fentanyl, opioid, cannabinoid, rimonabant, behavioral assays

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