A variety of drug discovery efforts are focused on creation of molecules that will increase nicotinic cholinergic neurotransmission to augment cognition in the dementias. In addition to the nicotinic system, GABAA receptors containing the a5 subunit (GABAA a5 receptors) can modulate hippocampal neurotransmission. Selective inhibition of GABAA a5 receptor function in the hippocampus enhances cognition in animal models of learning and memory, suggesting that inhibition of GABAA a5 may also be a viable therapeutic strategy. Like a7 nAChRs, the decline in GABAA a5 receptors is reported to be relatively spared in conditions like mild AD. Moreover, tests of selective modulators of either a7 nAChRs or GABAA a5 receptors show positive results in clinical studies for cognition and memory. Importantly, this suggests that two therapeutic targets that subserve learning and memory are preserved and functional in AD brains and can be targeted simultaneously. We have identified a dual allosteric modulator of both a7 nAChRs and GABAA a5 receptors, termed 522-054, synthesized under funding from our previous R21 grant (AG028800). The proposed work will support back-up compound optimization, initial drug safety assessment, chemistry scale-up, drug formulation, toxicological studies and submission of an IND application to the FDA using 522-054 as the initial lead preclinical development candidate. We will evaluate 522-054 and back-up compounds synthesized in the current proposal for: cross reactivity with other known receptor types, interaction with the hERG K+ channel (a predictor for cardiac QT prolongation), interaction with drug- metabolizing P450 cytochrome enzymes, plasma protein and p-glycoprotein transporter binding. These studies will help predict and eliminate candidate compounds that may have potential drug safety issues. When a lead candidate emerges from these drug safety studies we will identify a chemistry route that affords the simplest and most cost-effective means of synthesis. This optimized route will be used to produce GLP material for formal toxicological studies. An appropriate formulation will also be devised for toxicological studies to maximize exposure to levels of drug in the test species (dog, rodent, etc.) The toxicological studies will determine whether exposure to the drug causes significant toxicological events and its maximal tolerated dose. Successful completion of the proposed studies will culminate in the filing of an IND application with the FDA to initiate phase I clinical studies with the first dual allosteric modulator of nicotinic and GABAA receptors for treating the cognitive deficits of AD.
|Johnstone, Timothy B; Gu, Zhenglin; Yoshimura, Ryan F et al. (2011) Allosteric modulation of related ligand-gated ion channels synergistically induces long-term potentiation in the hippocampus and enhances cognition. J Pharmacol Exp Ther 336:908-15|