Adenylyl Cyclase 1 (AC1) Inhibitors as Opioid Alternatives for Chronic and Inflammatory Pain

National Center For Advancing Translational Sciences

Investigators

Abstract

Neuronal adenylyl cyclase 1 (AC1) is an enzyme that is highly expressed in neuronal tissues associated with pain processing and neuronal plasticity. Preclinical studies have shown that AC1 could be a promising target to treat chronic and inflammatory pain. Additional research in AC1 knockout mice suggested that an absence of AC1 revealed almost a complete loss in pain responsiveness, reduced the rewarding effects of opioids and opioid dependence. Despite promising observations in the literature, there is a need to further explore and validate AC1 as a pain target. This project is focused on the development and mechanistic characterization of AC1‐selective, central nervous system (CNS) penetrant small molecule inhibitors as a non‐opioid treatment for chronic pain. The team successfully miniaturized the cAMP HTRF assay for 1536-well plates. Over 56,000 compounds have been screened thus far; select hits from 30 different chemotypes were confirmed active by our collaborator. Blood-brain barrier (BBB) permeability and pharmacokinetics (PK) assays on these chemotypes are complete, and the team is following up on the top chemotypes. One of the lead compounds was evaluated in vivo and demonstrated some capacity to diminish acute pain. Eighty (80) analogs of the selected lead series were synthesized, and SAR is in progress. A GPCR-ome request was submitted to PDSP for one of the compounds. The team’s informatician identified potential AC1 binding sites and is exploring binding interactions at the CaM site and FSK binding pocket. Additionally, the team screened the first release of the NCI Natural Products Library (a copy is housed at NCATS); hits were fractionated by NCI and screened/counter screened at NCATS. Twenty-five natural products were selected for purification, and the distinct compounds were evaluated. Follow-up studies on six unique natural products chemotypes are underway