Mixed Kappa-Mu Opioids: Synthesis and Evaluation

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DESCRIPTION (provided by applicant): This is a competing revised renewal application to continue the syntheses and evaluation of mixed kappa/mu opioids that may be useful for the treatment of cocaine abuse and dependence. We have found that both acute and chronic treatment with the mixed k/¿ opioids - cyclorphan and butorphan (MCL-101) reduced cocaine self-administration dose-dependently and produced fewer side effects than k-selective agonists. In an effort to further extend the duration of action and to manipulate relative affinity and efficacy k and ¿ receptors, we propose innovative approaches to the synthesis of mixed k/¿ opioids. (1) Synthesis of morphinans with aminothiazole substitution of the phenol moiety in opioids. (2) Based on our success with the bioisosteric modifications of the N-alkyl and 3-hydroxyl functions of cyclorphan and MCL-101 that resulted in compounds with high affinity and selectivity at k/¿ receptors, our further investigation will be directed to the introduction of functional groups in the ring-C (cyclohexyl ring), and the synthesis of 3-amino- and 6-aminomorphinans. (3) The affinity and selectivity of new compounds will be determined by using radioligand binding assays that are selective for mu, delta, and kappa opioid receptors. (4) The efficacy of compounds to couple to G proteins will be determined by measuring [35S]GTPgS binding to membranes from Chinese hamster ovary (CHO) cells that are stably transfected with one of the human opioid receptors. (5) The mouse warm-water tail flick and writhing assays will be used to determine the potency and selectivity of new compounds in vivo. (6) Determine the dose-effect time course functions of selected compounds on basal and cocaine- potentiated brain stimulation using intracranial-stimulation (ICSS). These assays will result in the development of pharmacological profiles of compounds that will assist in identifying compounds that will be the best candidates to test in preclinical monkey studies that could be carried out at McLean Hospital under a separate grant. The proposed research will be conducted at two independent sites. The synthesis component and the intracranial-stimulation studies (ICSS) will be conducted at McLean Hospital under the direction of John L. Neumeyer, Ph.D. and Elena Chartoff, Ph.D., and the pharmacological evaluation component will be conducted at the University of Rochester under the direction of Jean M. Bidlack, Ph.D.