The Project Grant award R61NS133704, totaling $1,846,202.00, was provided by the National Institute of Neurological Disorders and Stroke under the Drug Abuse and Addiction Research Programs (CFDA 93.279) to Duke University. The primary objective is to develop potent, selective, and peripherally-restricted antagonists of the adrenergic receptor beta-3 (ADRB3) for the treatment of chronic primary pain conditions affecting over 100 million people. This will involve: 1) developing novel ADRB3 antagonists with improved potency, drug-like properties, and peripheral selectivity; 2) evaluating the ability of these antagonists to reverse COMT-dependent pain and nociceptor activity; and 3) establishing a multidisciplinary team to progress lead compounds towards human trials. Duke University has subcontracted a portion of the work under Aim 2 to RTI International to assist with the medicinal chemistry and pharmacological characterization of the ADRB3 antagonist compounds. The award commenced on September 8, 2023 with an expected completion date of August 31, 2025.