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Cyclazocine QSAR and Synthesis
Co-Investigator: Mark P. Wentland
Professor, Department of Chemistry and Chemical Biology Rensselaer Polytechnic Institute
A significant opportunity exists for cheminformatics to aid in the optimization of two series of cyclazocine analogues that have potential to treat cocaine addiction in humans. The general structures of these two series are represented by A and B and were made over the last several years to take advantage of the opioid-receptor interactive properties of our lead compound, cyclazocine (Wentland et al., 2001; Wentland et al., 2003). Cyclazocine is currently undergoing NIDA-sponsored clinical trials for the treatment of cocaine addiction (Pickworth et al., 2000) , however, the drug is known to be short acting due to O-glucuronidation. To address this and other deficiencies of cyclazocine, we prepared series A and B which are devoid of the problematical 8-phenolic hydroxyl group (Wentland et al., 2001; Wentland et al., 2003) . Historical structure-activity relationship (SAR) data for most opioid receptor interactive ligands, including the 2,6-methano-3-benzazocine (e.g., cyclazocine) class, dictate that a phenolic hydroxyl group is required for receptor binding. We recently found that a carboxamido group (-CONH 2) and certain amino groups (3-pyridinylamino) can replace this phenolic OH group on 2,6-methano-3-benzazocine and still display high affinity binding to opioid receptors. Of particular significance, is the observation that this novel carboxamido replacement may ameliorate the rapid clearance of opioids due to O-glucuronidation. In fact, we recently demonstrated that 8-carboxamidocyclazocine (8-CAC) has very high efficacy and a much longer duration of action (15 h) than cyclazocine (2 h) in mouse models of antinociception (Bidlack et al., 2002) .
While significant progress has been made in identifying highly affinic (for mu and kappa opioid receptors) and long acting compounds in vivo, our understanding of the relationship between structure and activity [binding affinity for mu and kappa opioid G-protein coupled receptors (GPCR)] has been slowed due to the lack of structural (e.g., X-ray) information. Only one X-ray structure of a GPCR has been published to date which involved the rhodopsin GPCR rather than an opioid receptor (Palczewski et al., 2000) . Several homology models for ligand binding to opioid receptors have been proposed (Mansour et al., 1997; Fowler et al., 2004) , however, there still exists uncertainty about the precise molecular interactions necessary for high binding affinity. Thus, molecular recognition between ligand and receptor must be studied by traditional structure-activity relationship (SAR) approaches - this involves hypothesis-driven serial synthesis of target compounds. This process is slow in that one must wait for binding data to be generated before a new analogue can be designed.
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