AMPAkines are modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and have been widely explored for a variety of neuropsychiatric diseases including schizophrenia and epilepsy (Chang et al., 2012 and Russo et al., 2012). Cognitive improvement has been the primary focus of most

research with this drug class (Hamlyn et al., 2009). Glutamate acting via AMPA receptors is essential for maintaining respiratory rhythmogenesis at the purported kernel of rhythm generation, the preBötzinger complex in the hindbrain (Funk et al., 1993 and Greer et al., 1991). Thus, the rationale for the use of AMPAkines to treat respiratory depression, in particular the type caused primarily by a decrease in respiratory VE821 rate (e.g., opioid-induced respiratory depression), is that positive allosteric modulators of AMPA receptors would enhance respiratory rhythm. Various AMPAkines

(Cortex Pharmaceuticals, Inc.) have been evaluated preclinically and clinically as respiratory IPI-145 manufacturer stimulants. The positive AMPA allosteric modulator CX546 reversed the ventilatory suppressive effects of fentanyl and phenobarbital in the rat (Ren et al., 2006). A second AMPA receptor modulator, CX717, has been tested pre-clinically and is also able to reverse the respiratory depressive effects of fentanyl, alcohol and pentobarbital (Ren et al., 2009 and Ren et al., 2012). CX717 also reverses opiate suppression of hypoglossal motor neurons (Lorier et al., 2010). In young healthy subjects with a target alfentanil infusion concentration of 100 ng/mL (i.e., analgesic), CX717 prevented the fall in respiratory rate vs. placebo (Oertel et al., 2010). However, in that study there also was an interaction

between alfentanil and CX717 with respect to visual analog scale parameter “tiredness”, in that the participants receiving CX717 reported increased tiredness compared to placebo controls. In humans, AMPAkines improved memory and information processing in the healthy elderly (Wezenberg et al., 2007) and people with schizophrenia (Goff et al., 2008). In a randomized, double-blind, crossover study in sleep deprived young subjects, CX717 enhanced cognitive performance and alertness (Boyle et al., 2012). Slow wave sleep was reduced and recovery sleep impaired. Thus, the respiratory stimulatory effects of new AMPAkine molecules are associated with Thymidine kinase stimulatory neuropsychiatric effects on arousal-alertness state and cognitive performance. It remains possible that dual effects of a single molecule on the neuropsychiatric and respiratory systems will limit the utility of these compounds as respiratory stimulants. Agents that increase the drive to breathe by mimicking the effects of acute hypoxia and/or hypercapnia at the level of the peripheral chemoreceptors represent a rational approach toward the development of therapeutics for breathing control disorders that would benefit from ventilatory stimulation.