GPR91 Activators

Chemicals classified as GPR91 Activators predominantly function through their influence on the citric acid cycle and SUCNR1, also known as GPR91. Primarily, these activators influence the levels of succinate, a key intermediate of the citric acid cycle and the primary agonist of this receptor. The activation of SUCNR1 is primarily dependent on the availability of succinate, and as such, the majority of these chemicals operate by increasing intracellular succinate concentrations.

Succinate and its analogs like dimethyl succinate, sodium succinate, and diethyl succinate can directly increase succinate availability. Fumarate and other upstream intermediates in the citric acid cycle, such as isocitrate and α-ketoglutarate, increase succinate levels indirectly by promoting its production. In contrast, malonate, itaconate, ethylmalonic acid, and 3-nitropropionic acid function by inhibiting succinate dehydrogenase, an enzyme responsible for the oxidation of succinate to fumarate in the citric acid cycle. By inhibiting this enzyme, these compounds increase the accumulation of succinate, leading to enhanced activation of SUCNR1. Therefore, the commonality among all these chemicals is their ability to increase intracellular succinate levels, either directly or indirectly, thus activating SUCNR1.