GENEVA, Switzerland—Tobacco use, which kills more than 5 million people per year, is responsible for one in 10 adult deaths. Nicotine significantly contributes to the addiction to tobacco smoking. Physical and emotional withdrawals often lead to high relapse and therapy failure in smoking cessation.
For those reasons, the news of a drug candidate that was effective in reversing somatic signs of withdrawal and the pain sensitivity known as hyperalgesia in mice created some buzz recently. In July, Addex Therapeutics, a biotechnology company involved in allosteric modulation-based drug discovery and development, announced positive results with its ADX71441 (GABAB receptor positive allosteric modulator) in preclinical models of nicotine addiction, further supporting the use of GABAB activation as a strategy to achieve smoking cessation. The study is part of an ongoing research collaboration with the U.S. National Institute on Drug Abuse (NIDA). The drug has not yet been tested on humans.
“These data are very promising and, combined with data already generated using ADX71441 in other addiction models, strongly support the development of ADX71441 in addiction,” said Sonia Poli, chief scientific officer of Addex, which is using its proprietary discovery platform to target receptors and other proteins that are recognized as essential for the therapeutic modulation of important diseases with unmet medical needs.
“Our collaboration with NIDA has provided invaluable information for the further development of ADX71441 in addiction, and an excellent example of our strategy to collaborate with government organizations, academia and patient groups in order to continue the development of our portfolio of drug candidates,” said Tim Dyer, CEO of Addex.
As Dyer explained, “Allosteric modulators are an emerging class of orally available, small-molecule therapeutic agents that may offer a competitive advantage over classical drugs. This potential stems from their ability to offer greater selectivity and better modulatory control at disease-mediating receptors.” Thus, they have the potential to be more specific and confer significant therapeutic advantages over conventional “orthosteric” small-molecule or biological drugs.
He added that most marketed drugs bind receptors where the body’s own natural molecular activators bind, specifically to a key part of each receptor’s anatomy called the active site. Thus, they have to compete with endogenous ligands in order to bind to the active site. Instead, allosteric modulators bind receptors at different sites and are not limited to just turning a receptor on and off; they can control the intensity of activation or deactivation while enabling the body to “retain its natural control over initiating receptor activation.”
ADX71441 is a potent selective positive allosteric modulator (PAM) that potentiates GABA responses at the GABAB receptor. It has demonstrated excellent preclinical efficacy and tolerability in several rodent models of pain, anxiety and addiction. Because the drug only acts when the natural ligand—GABA—activates the receptor and, therefore, respects the physiological cycle of activation, it has been proposed that PAMs produce less adverse effects and lead to less tolerance than direct agonists.
The study examined ADX71441’s effects on mecamylamine-precipitated physical and affective withdrawal signs in mice rendered dependent on chronic nicotine. As compared to saline-infused mice, nicotine-withdrawn mice showed a significant increased anxiety-related response, a significant increase in somatic signs and significant hyperalgesia. Oral treatment with ADX71441 at 1, 3 and 10 mg/kg administered 60 minutes prior to the precipitant, mecamylamine, dose-dependently reversed the somatic signs of withdrawal in nicotine-dependent mice. ADX71441 also reversed hyperalgesia at the highest dose of 10 mg/kg. The highest dose of ADX71441 alone did not precipitate withdrawal anxiety-like behavior, somatic signs or hyperalgesia in saline-treated mice. Overall, these data indicate that ADX71441 could alleviate the physical signs associated with nicotine withdrawal and help patients to achieve smoking cessation.
A recent article by Małgorzata Filip in Neuropharmacology reviews the therapeutic benefits in cocaine, nicotine, amphetamine and alcohol dependence of GABAB PAMs, further supporting the emerging role of GABAB activation as a strategy to achieve smoking cessation. The article claims that this class of drugs “may also benefit in mitigating the withdrawal from drugs of abuse.”