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Chronic Pain Nociceptin/Mu Bifunctional Agonists
New approaches for pain treatment are currently a critical unmet medical need. For chronic or neuropathic pain, opioid drugs, such as morphine, hydromorphone or oxycodone, are generally viewed as ineffective for relieving pain and put the patient at risk for dependence and addiction. In the era of the Opioid crisis, even the use of prescription opioids for acute or surgical pain is a risk factor for opioid addiction. The opioid crisis is in essence a double epidemic of opioid addiction and chronic pain. Over 25 million people have daily pain and over 2 million are addicted to opioids. New alternatives for safe, effective pain treatment are, as yet, unavailable to patients.
Compounds targeted to the nociceptin opioid receptor (NOP) have been known to modulate the pain and reward pharmacology of mu opioid (MOP) agonists. We have developed ‘bifunctional NOP/MOP agonists’ that have an attractive profile of potent analgesic effects, but lack opioid addictive potential, cause no dependence or respiratory depression. We recently reported such a profile for a novel NOP/MOP bifunctional agonist AT-121, which has partial agonist activity at NOP and MOP receptors (1).
Some of our other NOP agonists have shown efficacy superior to morphine, in a model of sickle cell pain (2), where morphine-like opioids may be contraindicated, and in models of neuropathic pain (3).
1. A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid effects in nonhuman primates
Ding H, Kiguchi N, Yasuda D, Daga PR, Polgar WE, Lu JJ, Czoty PW, Kishioka S, Zaveri NT, Ko MC
Science Translational Medicine. 2018 August 29
2. Small-molecule nociceptin receptor agonist ameliorates mast cell activation and pain in sickle mice
Vang D, Paul JA, Nguyen J, Tran H, Vincent L, Yasuda D, Zaveri NT, Gupta K
Haematologica. 2015 December
3. Differential effects of nociceptin/orphanin FQ (NOP) receptor agonists in acute versus chronic pain: studies with bifunctional NOP/μ receptor agonists in the sciatic nerve ligation chronic pain model in mice
Khroyan TV, Polgar WE, Orduna J, Montenegro J, Jiang F, Zaveri NT, Toll L
JJournal of Pharmacology and Experimental Therapeutics. 2011 November
Nicotinic Receptor Functional Antagonists
Relapse to smoking and poor quit rates are unaddressed concerns for a rising problem in cigarette and e-cigarette smoking. The primary unmet need in smoking cessation pharmacotherapy is the lack of ‘safe’ therapy for long-term abstinence. Currently available pharmacotherapy (varenicline, bupropion) do not block relapse, and are not approved for use beyond a 12-week regimen.
Astraea is developing a novel approach for smoking cessation pharmacotherapy with a new mechanism distinct from current anti-smoking medications. Our preclinical data shows that Astraea’s lead drug candidates prevent nicotine relapse in animal models, triggered by stress or by exposure to nicotine-associated cues (1). Additional preclinical data with Astraea’s lead candidate suggest that this pharmacological mechanism can block withdrawal symptoms associated with quitting drug intake not only of nicotine, but also morphine and tetrahydrocannabinol (2),(3). These data suggest that this approach may be promising for nicotine addiction and applicable to addiction to other abused substances.
1. The α3β4 nAChR partial agonist AT-1001 attenuates stress-induced reinstatement of nicotine seeking in a rat model of relapse and induces minimal withdrawal in dependent rats
Yuan M, Malagon AM, Yasuda D, Belluzzi JD, Leslie FM, Zaveri NT
Behavioral Brain Research. 2017 August 30
2. The α3β4* nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies
Muldoon PP, Jackson KJ, Perez E, Harenza JL, Molas S, Rais B, Anwar H, Zaveri NT, Maldonado R, Maskos U, McIntosh JM, Dierssen M, Miles MF, Chen X, De Biasi M, Damaj MI
British Journal of Pharmacology. 2014 August
3. Neuronal nicotinic acetylcholine receptors mediate ∆9 -THC dependence: Mouse and human studies
Donvito G, Muldoon PP, Jackson KJ, Ahmad U, Zaveri NT, McIntosh JM, Chen X, Lichtman AH, Damaj MI
Addiction Biology. 2018 October 31
Cocaine Addiction and Relapse
Nociceptin Receptor Agonists
Nociceptin agonists block the rewarding effects and relapse of a variety of abused drugs, including psychostimulants such as cocaine (1). We have shown that a small-molecule NOP agonist AT-312 attenuates the drug preference induced by cocaine in rodents (2). In preclinical models of cocaine relapse, we have also found that NOP agonists reduce relapse to cocaine triggered by stress and cocaine cues (3). Given that there are no approved pharmacotherapies to treat cocaine addiction and relapse, the preclinical results with NOP agonists are promising and warrant further investigation as a new approach for substance abuse disorders.
1. The Nociceptin Receptor as an Emerging Molecular Target for Cocaine Addiction
Lutfy K, Zaveri NT
Prog Mol Biol Transl Sci. 2016
Alcohol Addiction and Relapse
Nociceptin Receptor Agonists
There is significant pharmacological evidence showing dysregulation of the Nociceptin Opioid Receptor (NOP) system by chronic alcohol intake, linked to increased alcohol seeking and anxiety-like behavior. Nociceptin/orphanin FQ (N/OFQ), the endogenous peptide agonist of the NOP receptor, and small-molecule NOP agonists reduce the rewarding actions of alcohol and prevents reinstatement of alcohol seeking in preclinical models of alcohol use disorders in rodents. Furthermore, NOP agonists have anti-anxiety-like and anti-stress-like efficacy and can attenuate alcohol withdrawal symptoms and reverse the effect of stress in alcohol use relapse.
These preclinical findings strongly support the NOP receptor as a promising target for treating alcohol addiction with small-molecule, drug-like NOP receptor agonists for treating the various aspects of alcohol addiction (craving, withdrawal and relapse). In line with this pharmacological validation, Astraea Therapeutics has developed several novel classes of NOP agonists of which selected lead compounds show significant inhibition of alcohol preference in a mouse model of alcohol reward-induced place preference (1).
The goal of this project is to identify novel NOP agonists that can be advanced into human clinical testing for alcohol use disorders.