Effects of the stereochemical orientation of phenethylamines and imidazolines on alpha-adrenergic receptor-mediated DNA synthesis in primary cultured rat hepatocytes.
The hepatic alpha 1-adrenergic receptor mediates a variety of hepatic functions including respiration, glycogenolysis, gluconeogenesis, and growth. We have utilized a rat primary hepatocyte culture system to show that the alpha 1-adrenergic receptor can be activated in a stereoselective manner by a series of phenethylamines and catecholimidazolines resulting in the stimulation of DNA synthesis as determined by [3H]thymidine incorporation. The phenethylamines adhered to the Easson-Stedman hypothesis with a rank order of potency of (-)-(R)-norepinephrine (NE) greater than (+)-(S)-NE greater than the desoxy analog dopamine (DA) for the stimulation of DNA synthesis. However, the 2-substituted catecholimidazolines did not follow this trend and demonstrated an order of potency of the desoxy analog 3,4-dihydroxybenzyl imidazoline (DHT) greater than or equal to (-)-(R)-2-(3,4,alpha-trihydroxybenzyl)imidazoline (TBI) greater than (+)-(S)-TBI. 4-Substituted catecholimidazolines were less potent as inducers of DNA synthesis than the corresponding 2-substituted analogs with an order of potency of (+)-(R)-4-(3,4-dihydroxybenzyl)imidazoline (DBI) greater than (+,-)-(R,S)-DBI greater than (-)-(S)-DBI. When the beta-hydroxyl moiety of NE is replaced with an amino group as in 3,4-dihydroxyphenylethylenediamine, the isomers are less active than the beta-hydroxylated analogs and also demonstrate no stereoselectivity for the stimulation of DNA synthesis. These results demonstrate that the hepatic alpha 1-adrenergic receptor can recognize various isomeric forms of these compounds and that hepatocellular growth can be modulated in a stereoselective manner by phenethylamines and imidazolines.
Esbenshade
T A
TA
Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus 43210.
Hamada
A
A
Miller
D D
DD
Feller
D R
DR
D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004261:DNA Replication / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D010627:Phenethylamines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism
D007093:Imidazoles; D010627:Phenethylamines; D011942:Receptors, Adrenergic, alpha; D004247:DNA; D013936:Thymidine