Syntheses of (R)- and (S)-2- and 6-fluoronorepinephrine and (R)- and (S)-2- and 6-fluoroepinephrine: effect of stereochemistry on fluorine-induced adrenergic selectivities

S F Lu; B Herbert; G Haufe; K W Laue; W L Padgett; O Oshunleti; J W Daly; K L Kirk

doi:10.1021/jm990599h

Syntheses of (R)- and (S)-2- and 6-fluoronorepinephrine and (R)- and (S)-2- and 6-fluoroepinephrine: effect of stereochemistry on fluorine-induced adrenergic selectivities

J Med Chem. 2000 Apr 20;43(8):1611-9. doi: 10.1021/jm990599h.

Authors

S F Lu¹, B Herbert, G Haufe, K W Laue, W L Padgett, O Oshunleti, J W Daly, K L Kirk

Affiliation

¹ Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20893, USA.

PMID: 10780918
DOI: 10.1021/jm990599h

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

Adrenergic beta-Agonists / chemical synthesis
Adrenergic beta-Agonists / chemistry
Adrenergic beta-Agonists / metabolism
Animals
Binding, Competitive
Cerebellum / metabolism
Cerebral Cortex / metabolism
Epinephrine / analogs & derivatives*
Epinephrine / chemical synthesis
Epinephrine / chemistry
Epinephrine / metabolism
In Vitro Techniques
Norepinephrine / analogs & derivatives*
Norepinephrine / chemical synthesis
Norepinephrine / chemistry
Norepinephrine / metabolism
Radioligand Assay
Rats
Receptors, Adrenergic, alpha-1 / metabolism
Receptors, Adrenergic, alpha-2 / metabolism
Receptors, Adrenergic, beta-1 / metabolism
Receptors, Adrenergic, beta-2 / metabolism
Stereoisomerism
Structure-Activity Relationship

Substances

2-fluoroepinephrine
6-fluoroepinephrine
Adrenergic beta-Agonists
Receptors, Adrenergic, alpha-1
Receptors, Adrenergic, alpha-2
Receptors, Adrenergic, beta-1
Receptors, Adrenergic, beta-2
3-fluoronorepinephrine
6-fluoronorepinephrine
Norepinephrine
Epinephrine