| Abstract
| - To investigate the effect of the introduction of a 4-phenolic substituent on the δ opioid affinityand selectivity of the indolomorphinans, a range of 4-phenolic analogues of naltrindole wereprepared and evaluated in in vitro assays. Although the majority of the ligands displayed pooraffinity for all three opioid receptors (μ, κ, δ), 17-cyclopropylmethyl-6,7-didehydro-4-hydroxy-3-methoxy-6,7:2‘,3‘-indolomorphinan (13) was an exception, displaying excellent δ bindingselectivity (δ Ki = 7 nM, μ/δ = 1900, μ/κ = 1130). GTP-γ-S functional assays showed 13 to bea selective δ antagonist, albeit with lower potency than naltrindole. Although the reason forthe unique profile of 13 could not be determined, these results validate our approach ofintroducing groups into the indolomorphinans that are known to reduce μ activity, to obtainincreased δ selectivity.
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