Sensitivity of glycogen phosphorylase isoforms to indole site inhibitors is markedly dependent on the activation state of the enzyme

Background and purpose: Inhibition of hepatic glycogen phosphorylase is a potential treatment for glycaemic control in type 2 diabetes. Selective inhibition of the liver phosphorylase isoform could minimize adverse effects in other tissues. We investigated the potential selectivity of two indole site phosphorylase inhibitors, GPi688 and GPi819. Experimental approach: The activity of glycogen phosphorylase was modulated using the allosteric effectors glucose or caffeine to promote the less active T state, and AMP to promote the more active R state. In vitro potency of indole site inhibitors against liver and muscle glycogen phosphorylase a was examined at different effector concentrations using purified recombinant enzymes. The potency of GPi819 was compared with its in vivo efficacy at raising glycogen concentrations in liver and muscle of Zucker ( fa/fa ) rats. Key results: In vitro potency of indole site inhibitors depended upon the activity state of phosphorylase a . Both inhibitors showed selectivity for liver phosphorylase a when the isoform specific activities were equal. After 5 days dosing of GPi819 (37.5 μmol kg −1 ), where free compound levels in plasma and tissue were at steady state, glycogen elevation was 1.5‐fold greater in soleus muscle than in liver ( P <0.05). Conclusions and implications: The in vivo selectivity of GPi819 did not match that seen in vitro when the specific activities of phosphorylase a isoforms are equal. This suggests T state promoters may be important physiological regulators in skeletal muscle. The greater efficacy of indole site inhibitors in skeletal muscle has implications for the overall safety profile of such drugs. British Journal of Pharmacology (2006) 149 , 775–785. doi: 10.1038/sj.bjp.0706925