Authors:

Yu-Jun Chow

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About Paper:

Although the prevalence of substance use disorder (SUD) has declined in recent years, its complexity, driven by the difficulty of controlling illicit drug activity, continues to make it a persistent public health concern. In search of a treatment for SUD, aristoquinoline, an Aristotelia alkaloid, emerged as a promising candidate owing to its antagonistic activity at a3B4 nicotinic acetylcholine receptors (nAChR). Sub-desired selectivity and potency, however, required investigation into the structure—activity relationship (SAR). It has been through the design and application of a Direct-to-Biology (D2B) approach that the expansion of the aristoquinoline library for SAR studies has accelerated. Using this pipeline, >200 aristoquinoline analogues have been synthesized, quantified by NMR, and evaluated for antagonistic activity at the a3B4 nAChR subtype. Analogues identified as hits in the D2B approach were synthesized at a larger scale, purified, characterized, and reevaluated at the a3B4 nAChR to confirm antagonistic activity. This work demonstrated that this streamlined D2B pipeline successfully identifies SAR trends and led to a bigger aristoquinoline library for continuous SAR studies.

Source:

University of Illinois Chicago

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Co-authors:

Yu-Jun Chow