The main aim of this proposal is to seek safer alternatives to methadone from among the class of ligands identified in the present phase which in antinociceptive tests have full mu agonist efficacy and high potency but apparently bind irreversibly to opioid receptors and become morphine antagonists when the long lasting agonist effects have waned. Four identified candidates will be resynthesized and evaluated in binding in vitro and in vivo assays by collaborators at the University of Michigan and at the Medical College of Virginia. Further exploration of this class will involve synthesis of analogs of the 3-hydroxymorphinan derivative BU72 involving substitution of the phenyl ring, investigation of stereoselectivity, replacement of the pyrolidine bridge by tetrahydrofuran and the phenyl group by branched alkyl. It is also proposed to prepare morphinan and epoxymorphinan derivatives having similarly located aromatic rings with respect to ring A and the piperidine N-atom. It is proposed to evaluate opioids having kappa-agonist and opioid-antagonist actions as potential treatments for cocaine abuse by their effects in suppressing the behavioral sensitizing effects of cocaine. The target molecules will be N-CBM analogs of naltrindole with basic substituents in the indole aromatic ring. Selected candidates will be evaluated by Dr Toni Shippenberg of NIDA Intramural Research Division. It is proposed to have Professor Graeme Henderson, University of Bristol evaluate selected compounds from our present collection for activity at the orphan opioid receptor ORL. Should results justify it, a program of synthesis will be established.
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