Development of Adrb3 Antagonists for the Treatment of Pain

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PROJECT SUMMARY Chronic primary pain conditions (CPPCs) affect over 100 million people, yet remain ineffectively treated by conventional pharmacotherapies, such as opioids, that have poor efficacy and adverse central side effects. The goal of this proposal is to develop safer, more effective analgesics for patients with CPPCs. Specifically, we will develop potent, selective, peripherally-restricted antagonists of the adrenergic receptor beta-3 (Adrb3). Adrb3 is a G protein-coupled receptor that is activated by catecholamines. In clinical studies, we determined that patients with CPPCs such as fibromyalgia, low back pain, and irritable bowel syndrome have increased levels of catecholamines alongside reduced levels of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines). Consistent with clinical findings, our lab has shown that genetic or pharmacologic inhibition of COMT in rodents produces pain at multiple body sites via catecholamine activation of Adrb3 and its downstream effectors (eg, cytokines and p38 mitogen activated protein kinase) that promote inflammation and increase activity of pain-sensing nociceptors. Thus, Adrb3 is a novel and attractive target for the treatment of chronic primary pain. Yet, only a few antagonist tool compounds for Adrb3 exist, and even the most potent and selective antagonist L-748,336 has poor metabolic properties as identified by our preliminary pharmacokinetic studies. Further, additional work is needed to determine the ability of Adrb3 antagonists to reverse chronic primary pain. Thus, our objective is to develop a drug discovery platform for Adrb3 antagonists. To accomplish this, we propose to 1) develop novel Adrb3 antagonists based on the existing aryloxy propanolamine scaffold in L-748,337 with improved potency, drug-like properties, and peripheral selectivity, 2) test the ability of L-748,337 and newly synthesized Adrb3 antagonists to reverse COMT-dependent pain and nociceptor activity in the absence of side- effects (eg, addiction, cardiac, urinary), and 3) develop a multidisciplinary team with expertise in pain biology, medicinal chemistry, and drug development, regulation, and commercialization as well as clinical pain management, clinical trials, and patient advocacy to progress our lead-like compounds to a successful U19 therapeutics discovery platform. Successful completion of these studies will lead to the development of new peripherally-restricted analgesics that are suitable for advancement into human trials with the potential to have a positive impact on the quality of life for the millions who suffer from chronic primary pain.