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. 2024 Sep 19;29(18):4448.
doi: 10.3390/molecules29184448.

A Novel 5-Chloro- N-Phenyl-1 H-Indole-2-carboxamide Derivative as a Glycogen Phosphorylase Inhibitor: Evaluating the Long-Term Drug Effects on Muscle Function for the First Time

Yifan Zhao  1 , Zhiwei Yan  1 , Shuai Li  1 , Youde Wang  1 , Yachun Guo  2 , Tienan Wang  1 , Liying Zhang  1
Affiliations

A Novel 5-Chloro- N-Phenyl-1 H-Indole-2-carboxamide Derivative as a Glycogen Phosphorylase Inhibitor: Evaluating the Long-Term Drug Effects on Muscle Function for the First Time

Yifan Zhao et al. Molecules. .

Abstract

Compound 1 was previously identified by our team as a glycogen phosphorylase (GP) inhibitor with glucose-lowering activity and demonstrated to have protective effects against myocardial and cerebral ischemia. However, its impact on muscle function has not been clarified. This study is the first to evaluate the long-term effects of GP inhibitors on muscle function and metabolism. After a 28-day administration of Compound 1, we performed assays to assess muscle function and biochemical parameters in rats. We observed reductions in peak holding force, duration, tetanic contraction force, single-contraction force, and electromyographic signals under 20 s and 10 min contraction stimuli. The metabolic analysis showed no significant effects on muscle glycogen, ATP, lactic acid, and uric acid levels at low doses. In contrast, medium to high doses resulted in increased glycogen, decreased ATP, and reduced lactic acid (only at high doses), without affecting uric acid. These findings suggest that Compound 1 may adversely affect muscle function in rats, potentially due to the glycogen inhibition effects of GP inhibitors. This study provides crucial safety data and insights into the long-term effects of GP inhibitors on rat muscles, which will guide future developments and applications.

Keywords: GP inhibitors; adverse effects; diabetes; muscle energy metabolism; muscle function.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The structures of Compound 1 and Ingliforib.
Figure 2
Figure 2
The impact of Compound 1 on peak holding force (A) and holding duration (B) in rats. * p < 0.05; ** p < 0.01.
Figure 3
Figure 3
The impact of Compound 1 on the mechanical properties of load-bearing muscles in rats’ hindlimbs. Emg signals (A) and muscle tone (B) in the 20 s contraction protocol; Emg signals (C) and muscle tone (D) in the 10 min contraction protocol. * p < 0.05; ** p < 0.01; *** p < 0.001.
Figure 4
Figure 4
The impact of Compound 1 on rats’ muscle metabolism: (A) glycogen content; (B) ATP content; (C) LD content; (D) UA content. * p < 0.05; ** p < 0.01; *** p < 0.001.
See this image and copyright information in PMC

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