Inhibitors of the α3β4 nicotinic acetylcholine receptor (nAChR) are reported to reduce psychostimulant-seeking and self-administration in rodent models, making the α3β4 nAChR a promising target for addiction therapy. However, existing ligands for the α3β4 nAChR suffer from suboptimal pharmacokinetics and poor target-selectivity. Aristoquinoline (ARQ), an alkaloid isolated from <i>Aristotelia chilensis</i>, was recently reported to inhibit human α3β4 nAChR preferentially over other neuronal nAChR subtypes, making it an attractive starting point in the development of a selective and potent α3β4 nAChR inhibitor. In pursuit of this goal, we have established the first synthesis of ARQ employing a unique Ritter-like reaction. Efforts are currently directed towards synthesizing structural analogs of ARQ employing this approach. Additionally, the mechanism and kinetics of the Ritter-like reaction are being explored to improve enantioselectivity and afford access to structurally diverse ARQ analogs. To complement our synthetic efforts, a cell-based receptor assay was employed to characterize the activity of ARQ and its derivatives at the α3β4 nAChR.

Synthesis and evaluation of aristoquinoline analogs using a Ritter-like reaction

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.