In vivo activity of the thyroid hormone receptor beta- and α-selective agonists GC-24 and CO23 on rat liver, heart, and brain.
Thyroid hormone analogs with selective actions through specific thyroid hormone receptor (TR) subtypes are of great interest. They might offer the possibility of mimicking physiological actions of thyroid hormone with receptor subtype or tissue specificity with therapeutic aims. They are also pharmacological tools to dissect biochemical pathways mediated by specific receptor subtypes, in a complementary way to mouse genetic modifications. In this work, we studied the in vivo activity in developing rats of two thyroid hormone agonists, the TRβ-selective GC-24 and the TRα-selective CO23. Our principal goal was to check whether these compounds were active in the rat brain. Analog activity was assessed by measuring the expression of thyroid hormone target genes in liver, heart, and brain, after administration to hypothyroid rats. GC-24 was very selective for TRβ and lacked activity on the brain. On the other hand, CO23 was active in liver, heart, and brain on genes regulated by either TRα or TRβ. This compound, previously shown to be TRα-selective in tadpoles, displayed no selectivity in the rat in vivo.
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28029 Madrid, Spain.
Carmen
C
Grijota-Martínez
Eric
E
Samarut
Thomas S
TS
Scanlan
Beatriz
B
Morte
Juan
J
Bernal
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006827:Hydantoins / Q000494:pharmacology*; D007037:Hypothyroidism / Q000188:drug therapy; D008099:Liver / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D037021:Thyroid Hormone Receptors alpha / Q000819:agonists*; D037042:Thyroid Hormone Receptors beta / Q000819:agonists*; D014284:Triiodothyronine
C517607:5-(3,5-diiodo-4-(3-isopropyl-4-hydroxyphenoxy)benzyl)imidazolidine-2,4-dione; D000085:Acetates; D001559:Benzhydryl Compounds; C483767:GC 24 compound; D006827:Hydantoins; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine
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