P2‐255: Optimizing the therapeutic targeting of alpha7 nAChR for the treatment of Alzheimer's disease

Studies have shown that drugs targeting alpha7 nicotinic acetylcholine receptors (nAChR) can correct learning deficits and promote neuronal survival following lesions to the basal forebrain cholinergic pathways. This has led to the development of drugs targeting alpha7 nAChR now in clinical trials for the treatment of AD. Initially, drug development focused on subtype-selective partial agonists such as GTS-21 (DMXBA). More recently, alternative compounds have been discovered which function as alpha7-selective positive allosteric modulators (PAMs). Objectives: We sought to determine whether agonists and PAMs could be used in combination therapies. Human alpha7 nAChR were studied in Xenopus oocytes. We identified three distinct structural motifs that can be utilized to convert a non-selective nAChR agonist to an alpha7-selective agonist. One motif derives from the endogenous alpha7 agonist choline. A second tropane-like motif involves the addition of a methyl group. The third motif, utilized by most agents in clinical development, involves addition of a large hydrophobic side group such as a benzylidene. Specific elaborations on the benzylidene motif regulate potency, efficacy, and secondary desensitizing properties of the agonists. We have investigated a range of interactions between alpha7-selective agonists and both Type 1 and Type 2 PAMs, to test the feasibility of combination therapies. We found that if an alpha7-agonist, such as GTS-21, with strong secondary desensitizing properties, was combined with a Type 1 PAM such as 5-Hydroxyindole, the desensitization produced by GTS-21 negated the potentiating effects of the PAM. However, agonists like GTS-21 may synergize with Type 2 PAMs, which destabilize alpha7 receptor desensitization, resulting in prolonged large amplitude currents. Such strong interactions may result in over-stimulation of the receptors and diminish the therapeutic utility of such drug combinations. Optimized therapeutic targeting of alpha7 nAChR will have to encompass the considerations of numerous factors, including the selectivity, efficacy, and potency of specific agents, as well as potentially confounding effects related to the induction of stable desensitized states of the receptor. Additionally, the possible development of combination therapies with agonists and positive allosteric modulators will need to rely on the precise matching of select agonists to specific modulators.