Abstract
Several routes to the enantiomers of fluoronorepinephrines (1) and fluoroepinephrines (2) were explored. A catalytic enantioselective oxazaborolidine reduction and a chiral (salen)Ti(IV) catalyzed asymmetric synthesis of silyl cyanohydrins proved efficacious in the key stereo-defining steps of two respective routes. Binding studies of the catecholamines with alpha(1)-, alpha(2)-, beta(1)-, and beta(2)-adrenergic receptors were examined. The assays confirmed that fluorine substitution had marked effects on the affinity of (R)-norepinephrine and (R)-epinephrine for adrenergic receptors, depending on the position of substitution. Thus, a fluoro substituent at the 2-position of (R)-norepinephrine and (R)-epinephrine reduced activity at both alpha(1)- and alpha(2)-receptors and enhanced activity at beta(1)- and beta(2)-receptors, while fluorination at the 6-position reduced activity at the beta(1)- and beta(2)-receptors. The effects of fluorine substitution on the S-isomers were less predictable.
MeSH terms
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Adrenergic beta-Agonists / chemical synthesis
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Adrenergic beta-Agonists / chemistry
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Adrenergic beta-Agonists / metabolism
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Animals
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Binding, Competitive
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Cerebellum / metabolism
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Cerebral Cortex / metabolism
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Epinephrine / analogs & derivatives*
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Epinephrine / chemical synthesis
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Epinephrine / chemistry
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Epinephrine / metabolism
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In Vitro Techniques
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Norepinephrine / analogs & derivatives*
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Norepinephrine / chemical synthesis
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Norepinephrine / chemistry
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Norepinephrine / metabolism
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Radioligand Assay
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Rats
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Receptors, Adrenergic, alpha-1 / metabolism
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Receptors, Adrenergic, alpha-2 / metabolism
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Receptors, Adrenergic, beta-1 / metabolism
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Receptors, Adrenergic, beta-2 / metabolism
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Stereoisomerism
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Structure-Activity Relationship
Substances
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2-fluoroepinephrine
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6-fluoroepinephrine
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Adrenergic beta-Agonists
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Receptors, Adrenergic, alpha-1
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Receptors, Adrenergic, alpha-2
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Receptors, Adrenergic, beta-1
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Receptors, Adrenergic, beta-2
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3-fluoronorepinephrine
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6-fluoronorepinephrine
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Norepinephrine
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Epinephrine