3-Monoiodothyronamine: the rationale for its action as an endogenous adrenergic-blocking neuromodulator.

The investigations reported here were designed to gain insights into the role of 3-monoiodothyronamine (T1AM) in the brain, where the amine was originally identified and characterized. Extensive deiodinase studies indicated that T1AM was derived from the T4 metabolite, reverse triiodothyronine (revT3), while functional studies provided well-confirmed evidence that T1AM has strong adrenergic-blocking effects. Because a state of adrenergic overactivity prevails when triiodothyronine (T3) concentrations become excessive, the possibility that T3's metabolic partner, revT3, might give rise to an antagonist of those T3 actions was thought to be reasonable. All T1AM studies thus far have required use of pharmacological doses. Therefore we considered that choosing a physiological site of action was a priority and focused on the locus coeruleus (LC), the major noradrenergic control center in the brain. Site-directed injections of T1AM into the LC elicited a significant, dose-dependent neuronal firing rate change in a subset of adrenergic neurons with an EC(50)=2.7 microM, a dose well within the physiological range. Further evidence for its physiological actions came from autoradiographic images obtained following intravenous carrier-free (125)I-labeled T1AM injection. These showed that the amine bound with high affinity to the LC and to other selected brain nuclei, each of which is both an LC target and a known T3 binding site. This new evidence points to a physiological role for T1AM as an endogenous adrenergic-blocking neuromodulator in the central noradrenergic system.

Selective activation of thyroid hormone signaling pathways by GC-1: a new approach to controlling cholesterol and body weight.

The current report describes progress in development of a selective thyroid hormone receptor modulator, GC-1. This compound binds selectively to the beta-isoform of the thyroid hormone receptor, and its uptake into the heart is relatively low. Studies in rats, mice and monkeys show that GC-1 lowers cholesterol with 600- to 1400-fold more potency and approximately two- to threefold more efficacy than atorvastatin, a compound that blocks HMG-CoA reductase. GC-1 also decreases plasma levels of triglyceride and lipoprotein (a), and induces loss of fat. These effects can be observed under conditions where there is either no or minimal effect on heart rate, and no detectable loss of muscle. Although more study is required, compounds of this class deserve further investigation for treating lipid disorders and obesity.