Abstract
To investigate the effect of the introduction of a 4-phenolic substituent on the delta opioid affinity and selectivity of the indolomorphinans, a range of 4-phenolic analogues of naltrindole were prepared and evaluated in in vitro assays. Although the majority of the ligands displayed poor affinity for all three opioid receptors (mu, kappa, delta), 17-cyclopropylmethyl-6, 7-didehydro-4-hydroxy-3-methoxy-6,7:2',3'-indolomorphinan (13) was an exception, displaying excellent delta binding selectivity (delta Ki = 7 nM, mu/delta = 1900, mu/kappa = 1130). GTP-gamma-S functional assays showed 13 to be a selective delta antagonist, albeit with lower potency than naltrindole. Although the reason for the unique profile of 13 could not be determined, these results validate our approach of introducing groups into the indolomorphinans that are known to reduce mu activity, to obtain increased delta selectivity.
MeSH terms
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Animals
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Binding, Competitive
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Brain / metabolism
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Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
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Ileum / drug effects
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Ileum / physiology
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In Vitro Techniques
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Ligands
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Male
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Mice
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Mice, Inbred ICR
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Muscle Contraction / drug effects
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Muscle, Smooth / drug effects
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Muscle, Smooth / physiology
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Naltrexone / analogs & derivatives*
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Naltrexone / chemical synthesis
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Naltrexone / chemistry
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Naltrexone / pharmacology
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Narcotic Antagonists / chemical synthesis*
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Narcotic Antagonists / chemistry
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Narcotic Antagonists / pharmacology
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Rabbits
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Receptors, Opioid, delta / antagonists & inhibitors
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Receptors, Opioid, delta / metabolism*
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Vas Deferens / drug effects
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Vas Deferens / physiology
Substances
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17-cyclopropylmethyl-6,7-didehydro-4-hydroxy-3-methoxy-6,7-2',3'-indolomorphinan
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Indoles
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Ligands
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Narcotic Antagonists
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Receptors, Opioid, delta
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Guanosine 5'-O-(3-Thiotriphosphate)
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Naltrexone
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naltrindole