This application is focused on the synthesis and characterization of novel chiral 8-amino analogues of cyclazocine and ethylketocyclazocine (EKC) as new anti-cocaine and anti-heroin medications. Cyclazocine is a kappa opioid agonist and a mu opioid antagonist and is currently in a clinical trial as a possible medication for cocaine abuse. Kappa agonists and mu antagonists decrease dopamine release in the nucleus accumbens, a primary pathway involved in the reinforcing effects of drugs of abuse, and thus have the potential to treat drug abuse. Recently, EKC was shown to block cocaine self-administration in non-human primates. Therefore, derivatives of cyclazocine and EKC that do not have major side effects are potential medications for treating cocaine and heroin abuse in humans. Our earlier studies with racemic 8-aminocyclazocine analogues demonstrated that very good oral narcotic agonist and antagonist properties were seen in rodents. Recently, a small number of chiral derivatives in this series were made and characterized for binding to mu, delta, and kappa opioid receptors. Results from these studies support our hypothesis that opioid binding and in vivo efficacy can be improved relative to our lead compounds by first modifying R' of the 8-amino substituent (R'NH-) to provide probes to explore receptor space. We believe the NH (as H-bond donor) is required for binding. Emerging structure-activity relationship (SAR) data suggest that hydrophobic R' groups will be beneficial. Thus, we will make analogues with a broad spectrum of hydrophobicity to understand this aspect of SAR. After the first set of target compounds has been evaluated, we will use CoMFA to refine our refine our pharmacophore model allowing us to identify more potent analogues. Based on the excellent oral bioavailability of our lead compounds and our expectation that the desired pharmacological profile will be attained by rational medicinal chemistry design and synthesis, we have developed an extensive pre-clinical work- plan. Radioligand binding assays will be used to determine the affinity and selectivity of test compounds. Mouse antinociceptive tests, using selective agonists and antagonists, will be used to characterize the agonist and antagonist properties of the drugs. Also, microdialysis will be used to determine if selected compounds will inhibit cocaine-induced increases in dopamine levels in nucleus accumbens in rats. The characterization of novel cyclazocine derivatives will identify potential medications for treating cocaine and heroin abuse and will suggest the basic mechanisms responsible for the drug's action.
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