The brain α7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease: studies with DMXBA (GTS-21)

Abstract

A large decrease in brain nicotinic receptor levels occurs in Alzheimer's disease, relative to muscarinic and other receptors. Neurons possessing high affinity nicotinic receptors seem particularly vulnerable. The low affinity nicotinic receptors which selectively bind α-bungarotoxin are not significantly affected. The major nicotinic receptor subtype which binds this toxin is a homo-oligomer composed of α7 subunits. Due to its exceptionally high calcium ion selectivity, this particular receptor can be considered as a ligand-gated calcium channel. α7 receptors are found in regions of the brain which are important for cognition, including cerebral cortex and hippocampus. Hippocampal receptors are largely confined to GABAergic interneurons. α7 receptors seem less likely than α4–β2 receptors to be up-regulated in number and down-regulated in function as a result of chronic agonist exposure. A family of nicotinic agonists based upon the marine animal toxin anabaseine have been synthesized and investigated. One of these compounds, DMXBA [3-(2,4-dimethoxybenzylidene)-anabaseine; code name GTS-21] has displayed promising characteristics during phase I clinical tests. In the rat DMXBA is selectively agonistic upon α7 nicotinic receptors. In addition it is a moderately potent antagonist at α4–β2 receptors. DMXBA enhances a variety of cognitive behaviors in mice, monkeys, rats and rabbits. It also displays neuroprotective activity upon cultured neuronal cells exposed to β-amyloid or deprived of NGF. The compound is much less toxic than nicotine and does not affect autonomic and skeletal muscle systems at doses which enhance cognitive behavior. Phase I clinical tests indicate that large doses can be safely administered orally without adverse effects. Psychological tests on healthy young male subjects indicate a positive effect of DMXBA on some measures of cognition. While DMXBA is a much weaker partial agonist on human α7 receptors than upon rat α7 receptors, its 4-hydroxy metabolite has been shown to have excellent efficacy on both receptors. Thus, some of the physiological and behavioral effects of GTS-21 may be due to the actions of this primary metabolite.

Introduction

Cholinergic innervation of the cerebral cortex and hippocampus is particularly vulnerable to disruption in Alzheimer's disease (AD). There is a similar decrease in choline acetyltransferase, high affinity nicotinic receptor binding, and choline transporter sites in AD post-mortem brains [50], [60], [64], [69]. Whether the loss of these nicotinic receptors represents a primary lesion in the disease or simply occurs because these receptors may be largely localized on vulnerable neurons has not yet been completely resolved, but the concomitant loss of the other cholinergic components of the nerve terminal suggest that the latter possibility is the case. These results, along with the demonstration of cognitive behavioral deficits in animals treated with cholinergic antagonists and in lesioned animals, led to the formulation of the so-called ‘cholinergic hypothesis’, which emphasizes the consequences of preferential degeneration of the cholinergic projecting neurons in Alzheimer's dementia. A therapeutic corollary of this hypothesis is that treatments which reduce this cholinergic degeneration or counteract the resulting cholinergic hypofunction should be useful. Historically, this led first to the development of acetylcholinesterase inhibitors, which only in the past few years have been shown to provide some limited symptomatic benefit to AD patients. The second phase in cholinergic drug design for AD focused upon muscarinic receptor agonists, particularly M1 agonists, since muscarinic receptors are much more numerous (>50–100X) in the mammalian brain than are nicotinic receptors. Considerable interest in CNS nicotinic receptors developed when several laboratories almost simultaneously [6], [50], [60], [64], [69] reported drastic (≥50%) losses in cerebral cortex high affinity nicotinic receptors in AD, while changes in muscarinic receptors were relatively quite small [69]. Thus, CNS nicotinic receptors may be drug targets for treatment of AD and a variety of other disorders [14], [33], [38], [60].

In the past 5 years several nicotinic drug candidates have entered clinical tests for potential use in the treatment of AD. These may be broadly classified into two groups, based upon the particular type of nicotinic receptor subtype that is the drug's target. The initial drug group, including ABT-418 and nicotine, primarily targets nicotinic receptors containing the β2 subunit, of which α4–β2 is most abundant. The second group of drugs primarily target the predominant low affinity subtype, the α7 receptor. Stimulation of either receptor type has been shown to enhance cognitive behaviors in experimental animals. This article will focus upon the α7 nicotinic receptor as an AD drug target, summarize the therapeutic rationale for selecting this receptor target and present the current understanding of the properties of DMXBA (GTS-21), the first α7 nicotinic agonist drug candidate to be developed.