ABSTRACT Cocaine use disorder (CUD) is one the most common substance use disorders and affects 22.5 million people worldwide. CUD is associated with substantial morbidity and has been recognized as a risk factor for hypertension and stroke. CNS-related complications of CUD include cognitive impairment, behavioral changes, major depressive disorder, and aggressive behavior. Initiation of inflammatory cascades leading to persistent neuroinflammation is central to the CNS complications seen in CUD. Nucleotide binding domain, leucine-rich repeat pyrin domain containing protein 3 (NLRP3) inflammasome is shown to play a crucial role in CUD- associated neuroinflammation. Chronic use of cocaine leads to aberrant activation of the NLRP3 inflammasome. A key step in the activation process is a homotypic interaction between the pyrin domains in NLRP3 and an adapter protein, apoptosis-associated speck-like protein containing a CARD (ASC). NLRP3 activation leads to the release of pro-inflammatory cytokines, such as, interleukin-1 (IL-1) and IL-18, causing neuronal pyroptosis and death. Disruption of NLRP3 signaling via small molecules, such as MCC950, is reported to display beneficial effects in animal models of CUD. Our recent studies identified a small molecule NLRP3 inhibitor, AMS-17. AMS- 17 thwarted the LPS-induced NLRP3 activation in vitro and in vivo. Subsequent mechanistic analysis revealed that the NLRP3 inhibitory activity of AMS-17 is attributed to its ability to bind to NLRP3 pyrin domain, thus preventing the interaction between NLRP3 and ASC. This proposal is focused on developing AMS-17 analogues with improved biological activity, low toxicity, and high druglikeness. Aim 1 described in this proposal is focused on the computer-assisted design, synthesis and chemical characterization of AMS-17 analogues. Aim 2 will involve testing of the novel candidates in vitro using BV2 microglial cell line. We will also study the ability of the proposed compounds to penetrate the blood-brain barrier. The proposed studies are highly significant since they will provide new therapeutic options to minimize neurological complications of CUD. The proposal incorporates expertise in the area of synthetic medicinal chemistry (Dr. Kulkarni) and biological screening (Dr. Nekhai). It is expected to define NLRP3 inhibitory compounds working through a novel mechanism different from that of any other currently used drug.