LY404187 is a selective, potent and centrally active positive allosteric modulator of
AMPA receptors.
LY404187 preferentially acts at recombinant human homomeric GluR2 and GluR4 versus GluR1 and GluR3
AMPA receptors. In addition,
LY404187 potentiates the flip splice variant of these
AMPA receptors to a greater degree than the flop splice variant. In both recombinant and native
AMPA receptors, potentiation by
LY404187 displays a unique time-dependent growth that appears to involve a suppression of the desensitization process of these
ion channels.
LY404187 has been shown to enhance glutamatergic synaptic transmission both in vitro and in vivo. This augmentation of synaptic activity is due to the direct potentiation of
AMPA receptor function, as well as an indirect recruitment of voltage-dependent
NMDA receptor activity. Enhanced
calcium influx through
NMDA receptors is known to be a critical step in initiating long-term modifications in synaptic function (e.g., long-term potentiation, LTP). These modifications in synaptic function may be substrates for certain forms of memory encoding. Consistent with a recruitment of
NMDA receptor activity,
LY404187 has been shown to enhance performance in animal models of cognitive function requiring different mnemonic processes. These data suggest that
AMPA receptor potentiators may be therapeutically beneficial for treating cognitive deficits in a variety of disorders, particularly those that are associated with reduced glutamatergic signaling such as
schizophrenia. In addition,
LY404187 has been demonstrated to be efficacious in animal models of behavioral despair that possess considerable predictive validity for
antidepressant activity. Although the therapeutic efficacy of
AMPA receptor potentiators in these and other diseases will ultimately be determined in the clinic, evidence suggests that the benefit of these compounds will be mediated by multiple mechanisms of action. These mechanisms include direct enhancement of
AMPA receptor function, secondary mobilization of intracellular signaling cascades, and prolonged modulation of gene expression.