Abstract
The 1,5-dimethyl 3,7-diaza-3,7-dimethyl-9-oxo-2,4-di-2-pyridine-bicyclo[3.3.1]nonane-1,5-dicarboxylate, HZ2, has a high and selective affinity for the kappa opioid receptor and an antinociceptive activity comparable to morphine. In addition, it is characterized by a long duration of action and a high oral bioavailability. QSAR studies within series of kappa agonists revealed a chair-boat conformation of a double protonated HZ2 characterized by an almost parallel orientation of the C9 carbonyl group and the N7-H group and at least one aromatic ring to be the pharmacophoric arrangement. Structural variations showed that the pyridine rings in 2 and 4 position can be replaced with p-methoxy-, m-hydroxy- and m-fluoro-substituted phenyl rings. However, all other substituents have to be kept the same for a high affinity to the kappa receptor.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / chemistry
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3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / pharmacology
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Analgesics, Opioid / chemistry*
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Analgesics, Opioid / pharmacology
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Animals
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Brain / metabolism
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Carboxylic Acids / chemistry*
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Carboxylic Acids / pharmacology
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Ethylketocyclazocine / analogs & derivatives*
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Ethylketocyclazocine / chemistry
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Ethylketocyclazocine / pharmacology
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Models, Molecular
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Molecular Structure
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Pyridines / chemistry*
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Pyridines / pharmacology
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Quantitative Structure-Activity Relationship
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Rats
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Receptors, Opioid, kappa / agonists*
Substances
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1,5-dimethyl-3,7-diaza-3,7-dimethyl-9-oxo-2,4-di-2-pyridine-bicyclo(3.3.1)nonane-1,5-dicarboxylate
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Analgesics, Opioid
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Carboxylic Acids
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Pyridines
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Receptors, Opioid, kappa
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Ethylketocyclazocine
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3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
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ketazocine