Peripheral vs. Central GABAB Receptor Activation: Insights from ADX71943

The GABAB receptor's agonist, baclofen, has been recognized for its potential benefits in treating conditions such as pain, PTSD, alcohol dependence, overactive bladder, and gastroesophageal reflux disease. However, its limited use is due to its brief effectiveness and potential side effects. A new GABAB receptor positive allosteric modulator, ADX71943, has been introduced and is being studied for its properties.

In the laboratory, ADX71943 was tested for its pharmacological activity and selectivity using both recombinant and native GABAB receptors. Animal studies were conducted using the acetic acid-induced writhing test and formalin tests in mice and rats to evaluate pain responses. Additionally, the marble burying and elevated plus maze tests, along with other behavioral and physiological assessments, were employed to explore the compound's central nervous system effects.

The in vitro studies revealed that ADX71943 enhances the potency and efficacy of agonists when GABA is present and displays selectivity for the GABAB receptor. In the acetic acid-induced writhing test, ADX71943 reduced pain-related behaviors, an effect that was blocked by the GABAB receptor antagonist CGP63360. The compound also demonstrated pain reduction in the formalin test for both mice and rats. However, it did not affect behaviors in the marble burying and elevated plus maze tests, even at high plasma concentrations. Furthermore, ADX71943 had no impact on body temperature, rotarod performance, or spontaneous locomotor activity.

The conclusions drawn from these studies suggest that ADX71943 exhibits efficacy in conditions with a significant peripheral component, such as acute and chronic pain, without affecting those related to central nervous system-mediated anxiety-like responses or causing side effects. This makes ADX71943 a valuable tool for distinguishing between the peripheral and central effects of GABAB receptor activation.