New Antidepressant Drug of AMPA positive allosteric modulators

[Speaker] Mai Hatano:1
[Co-author] Waki Nakajima:1, Tetsu Arisawa:1, Tomoyuki Miyazaki:1, Takuya Takahashi:1
1:Physiology, Yokohama City University, Japan

AMPA receptor is one of the most important molecules controlling the neuronal activities. Dysfunction of AMPA receptors is believed to underlie some of psychiatric disorders. Recent studies have clarified that AMPA receptors expression is decreased in post-mortem brain of patients with major depressive disorder (Gibbons et al., 2012, Duric et al., 2013). Positive allosteric modulators (PAMs) enhancing AMPA receptors function have been developed toward patients with depression but the effects of PAMs on depression seem to be limited. Here we show that we success in developing a new type of PAMs targeting AMPA receptors improving the depressive phenotype of rodent depression model.
Firstly using LC-MS/MS screening method, we identified the compound X showing high transitional potency through Blood-Brain Barrier (BBB). Secondly, we synthesized another compound A showing much higher transitional potency compared to compound X. Thirdly, we also found that compound A is metabolized immediately in vivo. To improve this character, we newly-synthesized another compound B hydrolysis-resistant form of compound A. Electrophysiological experiments revealed that these three compounds increased AMPA receptors current in the CA3-CA1 synapses.
Previously we found the expression of AMPA receptors deceased in rodent depression model, Wistar Kyoto (WKY) rat by novel PET tracer recognizing AMPA receptor. To elucidate whether these compounds are effective on improving depressive phenotype of WKY rat, we performed forced swim test (FST) to examine anti-depressive effect of these compounds. Interestingly, compound A and compound B reduced immobility time in FST compared to vehicle and compound X. Surprisingly compound B reduced immobility time in FST compared to compound A.
Taken together, compound B may be the promising compound as a new type of anti-depressant drugs.

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