title: 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.
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.
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20893, USA.
authors.forename: S F
authors.initials: SF
authors.lastname: Lu
authors.forename: B
authors.initials: B
authors.lastname: Herbert
authors.forename: G
authors.initials: G
authors.lastname: Haufe
authors.forename: K W
authors.initials: KW
authors.lastname: Laue
authors.forename: W L
authors.initials: WL
authors.lastname: Padgett
authors.forename: O
authors.initials: O
authors.lastname: Oshunleti
authors.forename: J W
authors.initials: JW
authors.lastname: Daly
authors.forename: K L
authors.initials: KL
authors.lastname: Kirk
mesh_terms: D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004837:Epinephrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D066298:In Vitro Techniques; D009638:Norepinephrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C407515:2-fluoroepinephrine; C407514:6-fluoroepinephrine; D000318:Adrenergic beta-Agonists; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; C024882:3-fluoronorepinephrine; C024884:6-fluoronorepinephrine; D009638:Norepinephrine; D004837:Epinephrine