Abstract
A number of derivatives structurally related to cirazoline (1) were synthesized and studied with the purpose of modulating alpha2-adrenoreceptors selectivity versus both alpha1-adrenoreceptors and I2 imidazoline binding sites. The most potent alpha2-agonist was 2-[1-(biphenyl-2-yloxy)ethyl]-4,5-dihydro-1H-imidazole (7), whose key pharmacophoric features closely matched those found in the alpha2-agonist 2-(3-exo-(3-phenylprop-1-yl)-2-exo-norbornyl)amino-2-oxazoline (15). (S)-(-)-7 was the most potent of the two enantiomers, confirming the stereospecificity of the interaction with alpha2-adrenoreceptors. This eutomer was tested on two algesiometric paradigms and, because of the interaction with alpha2-adrenoreceptors, showed a potent and long-lasting antinociceptive activity, since it was abolished by the selective alpha2-antagonist RX821002.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic alpha-Agonists / chemical synthesis*
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Adrenergic alpha-Agonists / chemistry
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Adrenergic alpha-Agonists / pharmacology
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Adrenergic alpha-Antagonists / pharmacology
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Analgesics / chemical synthesis*
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Analgesics / chemistry
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Analgesics / pharmacology
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Animals
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Binding, Competitive
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Biphenyl Compounds / chemical synthesis*
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Biphenyl Compounds / chemistry
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Biphenyl Compounds / pharmacology
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Cell Line
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Cerebral Cortex / drug effects
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Cerebral Cortex / metabolism
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Humans
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Idazoxan / analogs & derivatives
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Idazoxan / pharmacology
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / metabolism
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Imidazoles / pharmacology
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Imidazoline Receptors
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In Vitro Techniques
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Kidney / drug effects
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Kidney / metabolism
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Male
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Mice
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Models, Molecular
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Rabbits
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Radioligand Assay
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Rats
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Receptors, Adrenergic, alpha-2 / drug effects*
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Receptors, Drug / metabolism
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Stereoisomerism
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Structure-Activity Relationship
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Vas Deferens / drug effects
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Vas Deferens / physiology
Substances
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2-(1-(biphenyl-2-yloxy)ethyl)-4,5-dihydro-1H-imidazole
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Adrenergic alpha-Agonists
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Adrenergic alpha-Antagonists
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Analgesics
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Biphenyl Compounds
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Imidazoles
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Imidazoline Receptors
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Receptors, Adrenergic, alpha-2
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Receptors, Drug
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2-methoxyidazoxan
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Idazoxan