Abstract
Devices) cell lines stably expressing either theOX1orOX2 receptor. Select compounds were assessed in a conditioned place preference assay. Results: A number of compounds showed low nanomolar potency at the OX1 receptor and excellent selectivity (>100-fold) over the OX2 receptor. Several structural features that are important for OX1 activity have been identified. For instance, as the size of substituents increases at the 7-position of the tetrahydroisoquinoline the OX1 potency also increases. When tested in vivo, a compound with good in vitro potency and OX1 selectivity alone did not have place conditioning effect but blocked the acquisition of conditioned place preference to methamphetamine in rats. Conclusions: Structure–activity relationship studies have resulted in several compounds that are potent and OX1 selective. One such compound showed promising effect against the rewarding effects of methamphetamine. These results will facilitate the development of potent and selective OX1 antagonists as medications for the treatment of drug addiction. Financial support: NIH grants DA032837 and DA026582.
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