A new class of drugs under development for Alzheimer's disease has taken a cue from one of the world's oldest drugs–nicotine.
The highly selective nicotinic receptor agonists (NRAs) have the potential to mimic, and surpass, the cognition-enhancing effects of nicotine without its cardiovascular or addictive side effects. Tantalizing evidence suggests that the engineered molecules could provide a therapeutic one-two punch for Alzheimer's patients: immediate cognitive improvement and protection against the amyloid β plaques and neurofibrillatory tangling that are the disease's hallmarks.
Brains of patients with Alzheimer's disease (AD) show another distinct characteristic: a significant loss of cholinergic neurons and acetylcholine receptors, in addition to the hallmark plaques and tangles, said Dr. Marwan Sabbagh, a neurologist and director of the Sun Health Research Institute's Cleo Roberts Center for Clinical Research in Sun City, Ariz. “Initially, it was thought that muscarinic receptors were selectively affected in Alzheimer's, but now we think that's not so,” he explained. “It seems that the nicotinic receptors are the ones that go.”
Nicotinic acetylcholine receptors (nAChRs) are activated by acetylcholine, but they also react to nicotine and structurally similar molecules. Two types of nAChRs, the α7 and the α4-β2, are richly distributed in areas of the brain targeted by Alzheimer's. Other types of nAChRs occur in skeletal muscle and gut tissue.
Postmortem studies have shown that up to 50% of nAChRs are lost in Alzheimer's brains. This is apparently related to the buildup of amyloid β plaques, which seem to preferentially attach to the α7 nAChRs, the type most highly expressed in the hippocampus and frontal cortex, Dr. Sabbagh said in an interview. “High affinity α4-β2 receptors are preferentially lost in AD but the α7 receptor is expressed in plaques. This suggests that the biological interaction between the nicotinic receptors and AD pathology is complex,” he said.
A selective nAChR agonist could improve cholinergic function in a couple of ways, Dr. Sabbagh said. The surviving receptors would become more sensitive to any available acetylcholine. And since nAChRs help modulate the flow of other neurotransmitters, boosting their function could improve levels of dopamine, norepinephrine, and γ-amino butyric acid as well.
But since nAChRs are distributed throughout many tissues, a compound that attaches nonselectively could be loaded with adverse effects. “The challenge is to develop a selective agonist that enhances the activity of the high-affinity receptors in the brain, but not the nicotinic receptors that occur in the muscles, the gastrointestinal tract, or anywhere else.”
Drug companies are hot on the trail of such compounds. At least three agonists that target receptors involved in cognitive impairment are in preclinical or clinical trials right now. These three are described in the following paragraphs.
Targacept Inc. of Winston-Salem, N.C., a spinoff company of tobacco giant R.J. Reynolds, is farthest along the developmental pipeline with its candidate, TC-1734. In 2004, the company completed two phase II safety trials of the drug for age-associated memory impairment and mild cognitive impairment, with a total 107 patients. According to the company Web site, the drug had positive effects on cognition.
Last month, Targacept completed a second trial in 193 cognitively impaired older adults, but company representatives declined to comment for this article, saying they were constrained by the quiet period surrounding their initial public stock offering in January.
Memory Pharmaceuticals Corp. of Montvale, N.J., recently announced positive findings from its phase I trial of MEM 3454 in 48 healthy young subjects. Cognitive performance, a secondary end point of this safety trial, significantly improved in those taking 15 mg daily, said David A. Lowe, Ph.D., the company's chief scientific officer.
The trial lasted 14 days and tested three doses (15 mg, 50 mg, and 150 mg). Only the 15-mg dose showed a statistically significant effect on cognition. “One particularly interesting observation was that the effect on day 13 was stronger than it was on day 2,” Dr. Lowe said in an interview. “This shows that the effect is sustained.” The company will proceed with a phase IIa trial later this year.
Abbott Laboratories has a number of NRAs in the works, said James Sullivan, Ph.D., the company's vice president of neuroscience research. ABT-089 had proceeded to phase II trials in adults with attention-deficit hyperactivity disorder, but is now back in the preclinical stage for additional toxicologic studies. The drug also has potential as an Alzheimer's therapy, Dr. Sullivan said.
Although there are no published data on neuroprotective effects of any of the NRAs in development, studies suggest that nicotine blocks the aggregation of amyloid β on neurons. If NRAs work the same way, they might reduce or prevent neuronal plaque buildup.