Addex Therapeutics, a leading company pioneering allosteric modulation-based drug discovery and development, announced positive results with ADX71441 (GABAB receptor positive allosteric modulator) in preclinical models of nicotine addiction. The results were generated as part of an ongoing research collaboration with the United States National Institute for Drug Abuse (NIDA).

The study with ADX71441 examined its effects on mecamylamine precipitated physical and affective withdrawal signs in mice rendered dependent on chronic nicotine. The study was conducted as described by Jackson et al. (2008). Compared to saline-infused mice, nicotine-withdrawn mice showed a significant increased anxiety-related response, a significant increase in somatic signs and significant hyperalgesia compared to vehicle controls.

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 behaviour, 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 Filip in Neuropharmacology (2014) 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.

"These data are very promising and combined with data already generated using ADX71441 in other addiction models, strongly supports the development of ADX71441 in addiction", said Sonia Poli, chief scientific officer of Addex. "We thank NIDA and their team for the great work they have done and look forward to continuing our collaboration."

"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 organisations, academia and patient groups to continue the development of our portfolio of drug candidates." said Tim Dyer, chief executive officer of Addex.

Scientific advances have revolutionised our understanding of addiction as a chronic, relapsing disease and not a moral failure. Drug addiction is a complex illness which is characterised by intense and, at times, uncontrollable drug craving, along with compulsive drug seeking and use that persist even in the face of devastating consequences.

Addiction affects multiple brain circuits, including those involved in reward and motivation, learning and memory, and inhibitory control over behavior. While a person initially chooses to take drugs, over time the effects of prolonged exposure on brain functioning compromise that ability to choose, and seeking and consuming the drug become compulsive, often eluding a person's self-control or willpower. Because drug abuse and addiction have so many dimensions and disrupt so many aspects of an individual's life, treatment is not simple. Addiction treatment must help the individual stop using drugs, maintain a drug-free lifestyle, and achieve productive functioning in the family, at work, and in society. Patients typically require long-term or repeated episodes of care to achieve the ultimate goal of sustained abstinence and recovery of their lives.

Tobacco use kills more than 5 million people per year. It is responsible for 1 in 10 adult deaths. Among the five greatest risk factors for death, it is the single most preventable cause of morbidity and mortality. Nicotine significantly contributes to the addiction to tobacco smoking. Physical and emotional withdrawals remain the main causes for high relapse and therapy failure in smoking cessation.

Activation of gamma-aminobutyric acid subtype B (GABAB) receptor, a Family C class of GPCR, is clinically & commercially validated. Generic GABAB receptor agonist, baclofen, is marketed for spasticity and some spinal cord injuries, and used for overactive bladder (OAB), but is not commonly used due to variety of side effects of the drug and rapid clearance. ADX71441 is a potent selective positive allosteric modulator (PAM) which potentiates GABA responses at the GABAB receptor. ADX71441 is a novel, first-in-class, oral, small molecules that has demonstrated excellent preclinical efficacy and tolerability in several rodent models of pain, anxiety, addiction and OAB and have also proven efficacy in a genetic model of Charcot-Marie-Tooth Type 1A disease (CMT1A). ADX71441 differs from the generic drug baclofen in that it is a positive allosteric modulator rather than an orthosteric agonist at the GABAB receptor. ADX71441 only acts when the natural ligand (GABA) activates the receptor, and therefore respecting the physiological cycle of activation. It has been proposed that PAMs produce less adverse effects and lead to less tolerance than direct agonists (May and Christopoulos 2003; Langmead and Christopoulos 2006; Perdona et al. 2011; Urwyler 2011; Gjoni et al., 2008; Ahnaou et al).