College of Medicine – Tucson Department of Pharmacology
When
Where
Arizona Health Sciences Center, Room 8403
1501 N. Campbell Ave., Tucson, AZ 85724
Or
Presenter Details
Lauren Slosky, PhD
Assistant Professor, Department of Pharmacology
University of Minnesota
Abstract
G protein-coupled receptors, or GPCRs, signal through one or more transducers, including 16 Gα proteins and 2 β-arrestins. The GPCR neurotensin receptor 1, or NTSR1, is a promising target for the treatment of substance use disorders, but clinical development of balanced NTSR1 agonists, which activate many of these transducers, is precluded by on-target side effects. A decade-long drug discovery effort has led to the identification of β-arrestin-biased allosteric modulators of the NTSR1 that more selectively reduce addiction-associated behaviors. Slosky will share the mechanism by which these compounds achieve their functional selectivity and, capitalizing on this mechanism, describe the design of new allosteric modulators with new activities. Minor changes to a single molecular scaffold targeting the receptor-transducer interface produced small molecules with distinct G protein subtype activation profiles and in vivo activities. Compounds discriminate between and within G protein families, suggesting the ability to engineer ligands with precise transducer selectivity and laying a foundation for targeted, pathway-selective drug discovery.