Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS). Modulation of glutamate activity, therefore, provides a means to regulate neuronal signaling.
A group of receptors in the CNS known as metabotropic glutamate receptors (mGlus) are critical in maintaining normal function of the glutamatergic system. Appello is developing novel, highly selective drugs that modulate specific mGlus to treat various CNS disorders.
With 8 subtypes of mGlus it is important to modulate only the specific mGlu subtype that will improve a particular CNS condition. This is accomplished through allosteric modulation.
Glutamate binds at a specific site on the mGlu receptor, the orthosteric binding site, common to all subtypes. Activators and inhibitors targeting this site are likely to affect all the mGlu subtypes. Allosteric modulators, however, bind at a separate site on the receptor. This allows for selective targeting of one mGlu subtype over others. Due to the high selectivity of these allosteric modulators, off-target activity and resulting side effects can be minimized.