Home » Key Drug Discovery Articles » Organogermanium compound, Ge-132, forms complexes with adrenaline, ATP and other physiological cis-diol compounds

Organogermanium compound, Ge-132, forms complexes with adrenaline, ATP and other physiological cis-diol compounds

Significance Statement

Living things contains many important cis-diol compounds, and some of these compounds act in cell-to-cell signalling. For example, extracellular ATP is used as a signal of cellular damage, and catecholamines are used as stress signals and stress hormones. These compounds share the elemental structure of cis-diols. Therefore, cis-diol compound signalling is essential for the maintenance of homeostasis.Moreover, these cis-diol compounds are triggers of pain and some other problems. For example, adrenaline, noradrenaline and dopamine are catecholamines. Additionally, the ribose structures of ATP, GTP, and UTP contain cis-diols, and di-phosphates, mono-phosphates and adenosine are all mono-ribonucleic acids, which also contain cis-diols. Moreover, RNA also contains a cis-diol at the 3′-terminal. We investigated the interactions between cis-diol compounds and the organic germanium compound 3-(trihydroxygermyl) propanoic acid, THGPA. Our data demonstrate that ATP-induced calcium influx in normal human epidermal keratinocytes is reduced by THGPA. THGPA is also known as Ge-132; this compound is very stable, and its safety has been confirmed.

Across the world, many medicines that target receptors (e.g., receptor antagonists) are being used. The blocking of signals at the level of the receptor causes side effects that are due to the blocking of the transduction of important signals. Here, we suggest targeting the ligand to maintain cellular function and reduces side effects. This concept could create new avenues of drug-development research that could benefit patients.

Moreover, our findings are specifically related to adrenaline and noradrenaline as stress signals. We expected that the complex formations of these important compounds will have many biological effects. THGPA, a monomer of Ge-132, has been reported many physiological and therapeutic effects, and we believe that these interactions are likely a major contributor to these effects.

There are many subtypes of receptors for ATP, adrenaline, noradrenaline and adenosine. Therefore, the receptor affinities of these cis-diol compounds are likely diverse, which implies these compounds likely have multiple physiological functions. Indeed, THGPA has many interesting effects. Controlling the strength of the interactions of molecules with structures similar to THGPA and ligands may be useful for a new type of health care. Ge-132 has many physiological effects; e.g., the activation of the immune response by Ge-132 has been reported in many studies. The experiments and results presented in this article may represent a breakthrough in novel drug design.

Organogermanium compound Ge132 forms complexes adrenaline ATP physiological cisdiol. Global Medical Discovery

Journal Reference

Future Med Chem. 2015;7(10):1233-46.

Nakamura T1, Shimada Y1,2, Takeda T1, Sato K1, Akiba M3, Fukaya H3.

Show Affiliations

1Asai Germanium Research Institute Co., Ltd. Suzuranoka, Hakodate, Hokkaido 042-0958, Japan.

2The United Graduate School of Agricultural Science, Iwate University, Morioka, Iwate 020-8550, Japan.

3Tokyo University of Pharmacy & Life Sciences, Horinouchi, Hachioji, Tokyo 192-0392, Japan.

Abstract

BACKGROUND:

In mammals, adrenaline and ATP are life-essential vicinal diol and cis-diol functional groups. Here, we show that interactions between a safe organogermanium compound and these cis-diol compounds have the potential to regulate physiological functions. In addition, we represent a possible new druggable target for controlling the action of cis-diol compounds.

RESULTS:

We analyzed a single crystal structure of organogermanium 3-(trihydroxygermyl)propanoic acid (THGPA), a hydrolysate of safe Ge-132, in complex with catecholamine (adrenaline and noradrenaline), and evaluated the affinity between several cis-diol compounds and THGPA by NMR. An in vitro study using normal human epidermal keratinocytes was performed to investigate the inhibition of cis-diol compound-stimulated receptors by THGPA. At high concentration, THGPA inhibited the calcium influx caused by adrenaline and ATP.

CONCLUSION:

This study demonstrates that THGPA can modify cis-diol-mediated cell-to-cell signaling.

Go To Future Med Chem.