Ion channel modulators that enhance acetylcholine release: potential therapies for Alzheimer's disease

Enhancing the release of acetylcholine (ACh) in the brain is one approach to increasing neuronal activity, restoring central cholinergic tone and improving attention and cognition. ACh release is modulated by both ligand-gated (gamma-amino butyric acid A receptors/benzodiazepine [GABA(A)/BDZ], nicotinic-acetylcholine and serotonin, 5-HT3) and voltage-gated (calcium and potassium) ion channels. Of the ligand-gated channel modulators, the BDZ receptor (BDZR) inverse agonists (beta-CCM, ZK 93426) enhance activity-dependent release in animals, whereas S-8510, a partial inverse agonist, and the BDZR antagonist, flumazenil, show enhancement regardless of the behavioural state of the animal. Some of these agents have undergone limited clinical evaluation for Alzheimer's disease (AD) (ZK 93426, flumazenil, S-8510), but their potential anxiogenic liability makes their therapeutic use uncertain until more clinical data are available. Within the group of nicotinic agonists, ABT-418, though less potent than nicotine and epibatidine in promoting ACh release in vitro, was clinically evaluated based on its in vivo profile. Its lack of oral bioavailability has limited its acceptability, though transdermal administration has been used to circumvent this deficiency. Serotonin 5-HT3 receptor modulators have not been advanced for clinical evaluation for the treatment of AD. Among the voltage-gated ion channel modulators affecting L- or N-type calcium channels, nefiracetam, a nootropic agent, also increased ACh release in animal studies. It is currently undergoing clinical evaluation for AD, though a need for more potent and brain selective calcium channel blockers exists. Potassium channel modulators have been the most studied ACh release enhancing agents and several of these compounds (4-AP, 3,4-DAP, linopirdine) have been clinically evaluated. In AD patients, 4-AP, an A-type K+ channel blocker, elicited inconsistent and unremarkable effects. Linopirdine, whose enhancement of ACh release correlates with its ability to block M-type K+ channels, also produced disappointing clinical results, which may have been related to its suboptimal pharmacokinetic profile. Further work in this series has provided a compound (DMP 543) that should be a more reliable indicator of whether a blocker of this ion channel can activate the cholinergic system in man. This agent is currently undergoing clinical evaluation for AD.