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nAChR 2009: Move Over, Agonists; Make Way for Modulators

Adapted from a story that originally appeared on the Alzheimer Research Forum.

This is Part 2 of a three-part series. See also Parts 1 and 3.

6 November 2009. At a satellite symposium, “Nicotinic Acetylcholine Receptors (nAChRs) as Therapeutic Targets,” held days before the Society of Neuroscience’s annual meeting in Chicago last month, clinical discussion of cognitive treatments focused largely on nAChR agonists. Clearly, though, the arena of potential compounds has expanded. Mirroring a trend seen in muscarinic AChR drug development, the newest nAChR compounds are positive allosteric modulators (PAMs), which avoid the neurotransmitter site and instead bind alternate regions on the nicotinic AChR.

Though PAMs have yet to strut their stuff in the clinic, many in the field suspect they have an edge over agonists. Nicotinic AChRs desensitize with repeated stimulation at the neurotransmitter binding site, so a nagging problem with agonists has been that they induce tolerance and thereby lose effectiveness over time.

In an overview of advances in α7 PAMs, John Dunlop of Wyeth Research in Princeton, New Jersey, noted that in preclinical studies, the efficacy profile for PAMs parallels that of agonists. α7 PAMs can correct deficits in sensory gating (see, e.g., Hurst et al., 2005 and Ng et al., 2007) and prepulse inhibition (Dunlop et al., 2009)—two noted endophenotypes that serve as electrophysiological biomarkers in schizophrenics. Modulators have also shown cognitive enhancement in vivo, for example, in rats subjected to water-maze learning tasks (Timmermann et al., 2007).

However, one perceived disadvantage of PAMs is their reliance on cholinergic transmission, which may already be sagging in Alzheimer disease and other conditions. This could also be viewed as an advantage, some scientists say, because it means PAMs do not “create” additional signaling but rather amplify normal nAChR signaling—a feature that may be favorable for long-term use. Furthermore, some PAMs, namely those classified as Type 1, may do little for the tolerance problem that plagues agonists, because only Type 2 PAMs slow receptor desensitization, said Vince Simmon, CEO of Xytis, a private biotech company in Irvine, California. But Type 2 PAMs are a double-edged sword in another way. In order to reduce desensitization rates, they gate large amounts of Ca2+, which could have neurotoxic effects, as was the case with Pfizer’s PNU-120596 and Eli Lilly’s ampakine drug LY-503430, Simmon said. Type 1 PAMs only induce a moderate, that is, two- to threefold, increase in Ca2+ influx and maintain the quick receptor desensitization, which implies they may be less potent as agonists but possibly better because they do not create extra signaling. All told, scientists said it is too early to predict whether the ideal α7 compound would be an agonist or a PAM.

Thus far, one α7 PAM has gained clearance from the U.S. Food and Drug Administration to enter clinical development. It is compound XY4083, made by Xytis. The company has published preclinical data on this Type 1 PAM (Ng et al., 2007) but did not present new findings at the recent nAChR symposium. Nor has it begun Phase 1 trials of the compound, despite having gained FDA approval for such studies in November 2008. “We are looking for financing and/or partnership,” Simmon told ARF in a phone interview. The decision about which disease(s) to target would be made with a partner, but at this point the company is leaning toward standard-of-care therapy in schizophrenia as a first indication. “With schizophrenia, there are short-term tests that can be done for cognition, for example, sensory gating. Whereas in AD, you have to do pretty long-term studies to see effects,” Simmon said. At the nAChR symposium, posters described α7 PAMs in preclinical development at Johnson & Johnson (JNJ-1930942), Abbott (A-716096), Roche (dimethylcyclopropyl-benzamides), and GlaxoSmithKline (PheTQS).

Puff, puff
A presentation by Paul Newhouse of the University of Vermont, Burlington, provided a respite from the flood of αnumeric compound names. Rather than boosting cognitive function by tickling nAChRs with agonists or modulators, his team recruited people with mild cognitive impairment (MCI) for a pilot trial of a physiological nAChR substrate—nicotine itself.

Motivation for this trial came from earlier work by Newhouse and others showing that cholinergic mechanisms help mediate age-related shifts in the way our brains handle cognitive tasks. These studies tested predictions extending from the Resource Reduction Hypothesis, which presumes that reduced efficiency in lower-level core processes (e.g., attention, working memory, speed of memory) leads to higher-level impairments (e.g., decision making, language, problem solving). Researchers have found that people compensate for age-induced declines in core processes by increasingly shifting cognitive processing forward in the brain. As such, elders performing at the same level as younger people show more activity in frontal brain structures. Blockage of nicotinic or muscarinic AChRs with antagonists can reproduce this effect in young people, suggesting that the cholinergic system is involved in this caudal to frontal shift (aka the PASA effect).

On these grounds, Newhouse and colleagues simply asked whether nicotine, in this case offered through skin patches, would provide any measurable cognitive boost to MCI patients whose nAChR function is presumably better preserved than that of people with outright AD. Their study, which was funded by the National Institute on Aging (NIA), enrolled 74 non-smokers with amnestic MCI at three sites for a six-month double-blinded study, followed by a six-month open-label extension. During the double-blinded phase, the treatment group showed improvement on various measures including delayed word recall accuracy, choice reaction time, and speed of memory. “If we saw cognitive improvement, we did not lose that effect over the relatively lengthy trial,” Newhouse said. The study had no major drug-related adverse events, though the nicotine-treated group did end up with lower blood pressure. Curiously, the treatment effects were more prominent in ApoE4 homozygotes compared to people with the ApoE3 allele or just one copy of E4. Thirty of 70 participants in that MCI trial had at least one E4 allele. At the Cognitive Neuroscience Society’s annual meeting held in San Francisco earlier this spring, UK researchers (Marchant et al.) also reported E4 preferential benefit to young people (ages 18-30) treated with a nicotine nasal spray. In a separate trial presented by Newhouse at the nAChR symposium, nicotine improved several core cognitive deficits in non-smoking adolescents with attention deficit hyperactivity disorder (ADHD). And recently, Pfizer has moved varenicline (a nicotinic receptor partial agonist sold under trade name Chantix for smoking addiction) into a Phase 2 trial of mild to moderate AD patients. For more on mechanisms behind cognitive enhancement, see Part 3.—Esther Landhuis.

This is Part 2 of a three-part series. See also Parts 1 and 3.

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