This is a competing renewal application to continue the synthesis 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 kappa/mu opioids - cyclorphan and its n-cyclobutylmethyl derivative, MCL-101, reduced cocaine self-administration dose-dependently and produced fewer side effects than kappa-selective agonists. In an effort to further extend the duration of action and to manipulate relative affinity and efficacy at kappa and mu receptors, we propose three innovative approaches to the synthesis of mixed kappa/mu opioids: (1) Synthesis of morphinans with aminothiazole bioisosteric substitution of the phenol moiety in opioids;(2) Synthesis of bivalent morphinans. Efforts will be directed to establish the optimum morphinan pharmacophores;determine the optimal site on the pharmacophore connecting the linkers;vary the type of linkers;and establish the optimal length of the linkers;and (3) 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 at kappa/mu receptors, our further investigation will be directed to the introduction of functional groups in the ring-C (cyclohexyl ring). The compounds we propose to make include: the 6-amino/6-hydroxyl morphinans;6-oxa and 8-oxa morphinans;and their analogues. 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. The efficacy of compounds to couple to G proteins will be determined by measuring [35S]-GTPgammaS binding to membranes from Chinese hamster ovary (CHO) cells that are stably transfected with one of the human opioid receptors. The mouse warm-water tail flick and writhing assays will be used to determine the potency and selectivity of new compounds in vivo. These assays will results in the development of pharmacological profiles of compounds that will assist in identifying compounds that will be the best candidates to test in the preclinical monkey studies. The proposed research will be conducted at two independent sites. The medication synthesis component will be conducted at the McLean Hospital under the direction of John L. Neumeyer, Ph.D., and the pharmacological evaluation component will be conducted at the University of Rochester under the direction of Jean M. Bidlack, Ph.D.
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