An article co-authored by UF Department of Pharmacology and Therapeutics Professor Roger Papke, Ph.D., was published in the newest edition of the Journal of Biological Chemistry.
Papke collaborated on the article, “Critical molecular determinants of α7 nicotinic acetylcholine receptor allosteric activation: separation of direct allosteric activation and positive allosteric modulation,” with faculty from the University of Florida Department of Chemistry and the Northeastern University Department of Pharmaceutical Sciences.
From the abstract:
The α7 nicotinic acetylcholine receptors (nAChRs) are uniquely sensitive to selective positive allosteric modulators (PAMs), which increase the efficiency of channel activation to a level greater than that of other nAChR. While PAMs must work in concert with “orthosteric” agonists, compounds such as GAT107 ((3aR,4S,9bS)-4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) have the combined properties of agonists and PAMs (ago-PAMs) and produce very effective channel activation (direct allosteric activation, DAA) by operating at two distinct sites in the absence of added agonist. One site is likely to be the same transmembrane site where PAMs like PNU-120596 function. We show that the other site, required for direct activation, is likely to be solvent accessible at the extracellular domain vestibule. We identify key attributes of molecules in this family that are able to act at the DAA site through variation at the aryl ring substituent of the tetrahydroquinoline ring system and with two different classes of competitive antagonists of DAA. Analyses of molecular features of effective allosteric agonists allow us to propose a binding model for the DAA site, featuring a largely non-polar pocket accessed from the extracellular vestibule with an important role for the Asp 101. This hypothesis is supported with data from site-directed mutants. Future refinement of the model and the characterization of specific GAT107 analogs will allow us to define critical structure elements which can be mapped onto the receptor surface for an improved understanding of this novel way to target α7 nAChR therapeutically.
The full article can be viewed here.