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Effects of the stereochemical orientation of phenethylamines and imidazolines on α‐adrenergic receptor‐mediated dna synthesis in primary cultured rat hepatocytes
Author(s) -
Esbenshade Timothy A.,
Hamada Akihiko,
Miller Duane D.,
Feller Dennis R.
Publication year - 1992
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530040504
Subject(s) - chemistry , phenethylamines , stereoselectivity , imidazoline receptor , stereochemistry , stimulation , dna synthesis , receptor , glycogenolysis , adrenergic , phenylethanolamine , dna , pharmacology , medicine , biochemistry , metabolism , enzyme , tyrosine hydroxylase , catalysis
The hepatic α 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 α 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 [ 3 H]thymidine incorporation. The phenethylamines adhered to the Easson–Stedman hypothesis with a rank order of potency of (–)‐(R)‐norepinephrine (NE) > (+)‐(S)‐NE > 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) ≥ (–)‐(R)‐2‐(3,4,α‐trihydroxybenzyl)imidazoline (TBI) > (+)‐(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) > (+, –)‐(R,S)‐DBI > (–)‐(S)‐DBI. When the β‐hydroxyl moiety of NE is replaced with an amino group as in 3,4‐dihydroxyphenylethylenediamine, the isomers are less active than the β‐hydroxylated analogs and also demonstrate no stereoselectivity for the stimulation of DNA synthesis. These results demonstrate that the hepatic α 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. © 1992 Wiley‐Liss, Inc.