ORGN 15 |
| We have recently reported a series of 2,3:4',5'-aminothiazolomorphinans by functional replacement of the phenol moiety of morphinans (e.g. cyclorphan) with an aminothiazole function. Among this series, one compound ATPM (Figure 1) has been identified possessing high affinity at kappa receptor (Ki = 0.049 nM), and a kappa/mu selectivity of 30. The [35S]GTPgammaS binding studies showed that this compound is a full kappa agonists with both agonist and antagonist activities at mu receptor (Zhang, A. et al, J. Med. Chem. 47, 1886, 2004). This novel compound may represent a new generation of kappa agonist. In view of the potential utility of kappa receptor ligands and the promising results from 2,3:4',5'-aminothiazolomorphinan ATPM, we decided to launch a program evaluating a novel series of 6,7:4',5'-aminothiazolo and 6,7:2',3'-indolomorphinans. In this series, an aminothiazole or indole function will be installed in the ring-C of morphinans which was generally considered as a hydrophobic binding site at the opioid receptor, while retaining the H-bond binding site of phenol moiety.The synthesis was conducted from codeine in 10 steps and will be presented in detail. The complete biological assays of these novel compounds are not currently available, and will be reported elsewhere. (Supported by NIH Grants DA 14251).
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Heterocycles and Aromatics
8:00 AM-12:00 PM, Sunday, 13 March 2005 Convention Center -- Room 11A, Oral
Division of Organic Chemistry |
