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Optimization of the NanoBRET Platform for a Screen of Selective Adenylyl Cyclase 8 Inhibitors to Treat Alcohol Use Disorders (Abstract ID: 226063)
Abstract   Peer reviewed

Optimization of the NanoBRET Platform for a Screen of Selective Adenylyl Cyclase 8 Inhibitors to Treat Alcohol Use Disorders (Abstract ID: 226063)

Milo Garceau, Val J. Watts and Dave Roman
The Journal of pharmacology and experimental therapeutics, Vol.393(5 Supplement), 104146
05/2026
DOI: 10.1016/j.jpet.2026.104146

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Abstract

Adenylyl cyclase 8 (AC8) is a membrane-bound protein that catalyzes the formation of cAMP from ATP. AC8 has been implicated in various neurological disorders, including alcohol use disorders (AUDs), with the knockout of AC8 showing decreases in alcohol seeking behaviors. Attempts to inhibit AC8, however, have proven challenging. As a member of the adenylyl cyclase family, achieving selective inhibition of AC8 is at the root of this challenge. To achieve selective inhibition of AC8 over other AC isoforms, we have focused on disrupting calmodulin (CaM) mediated activation of AC8. This mechanism of activation is shared only by one other isoform: AC1. The binding sites of CaM on AC8 and AC1 are not conserved, and their differences provide hope that selective inhibition is possible. Identifying a selective and efficacious inhibitor of the AC8-CaM interaction could provide a novel first-in-class molecule that shows selectivity for AC8 inhibition to treat AUDs. To accomplish this, we are developing a high-throughput screen using NanoBRET to identify inhibitors of the AC8-CaM PPI.

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