Syntheses of 2,5- and 2,6-difluoronorepinephrine, 2,5-difluoroepinephrine, and 2,6-difluorophenylephrine: effect of disubstitution with fluorine on adrenergic activity.
Synthetic routes to difluorinated analogs of the adrenergic agonists, norepinephrine (NE), epinephrine (E), and phenylephrine (PE) have been developed. The syntheses were based on elaboration of the ethanolamine side chains from the appropriately polyfunctionalized benzaldehydes. The benzaldehydes were prepared from precursor difluorinated benzenes by sequential regioselective lithiations and reaction with electrophiles to introduce hydroxyl and carboxaldehyde functionalities. Binding and functional assay data demonstrate that the 2,6-difluorinated analogs are relatively inactive at both alpha- and beta-adrenergic receptors. These results are consistent with earlier observations that 2-fluoro substitution of adrenergic agonists decreases alpha-adrenergic activity whereas 6-fluoro substitution decreases beta-adrenergic activity.
Chen
G T
GT
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
King
M
M
Gusovsky
F
F
Creveling
C R
CR
Daly
J W
JW
Chen
B H
BH
Nie
J Y
JY
Kirk
K L
KL
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004146:Dioxanes / Q000378:metabolism; D004837:Epinephrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D017611:Fluorine Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D007295:Inositol Phosphates / Q000378:metabolism; D009638:Norepinephrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010656:Phenylephrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011224:Prazosin / Q000378:metabolism; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism
D004146:Dioxanes; D017611:Fluorine Compounds; D007295:Inositol Phosphates; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D010656:Phenylephrine; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D009638:Norepinephrine; D011224:Prazosin; D004837:Epinephrine