Faculty Collaboration Database

Lipid Trolling to Optimize A₃ Adenosine Receptor-Positive Allosteric Modulators (PAMs). J Med Chem 2024 Jul 25;67(14):12221-12247

Date

07/03/2024

Pubmed ID

38959401

Pubmed Central ID

PMC11636968

DOI

10.1021/acs.jmedchem.4c00944

Scopus ID

2-s2.0-85197620924 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

A₃ adenosine receptor (A₃AR) positive allosteric modulators (PAMs) (2,4-disubstituted-1H-imidazo[4,5-c]quinolin-4-amines) allosterically increase the E_max of A₃AR agonists, but not potency, due to concurrent orthosteric antagonism. Following mutagenesis/homology modeling of the proposed lipid-exposed allosteric binding site on the cytosolic side, we functionalized the scaffold, including heteroatom substitutions and exocyclic phenylamine extensions, to increase allosteric binding. Strategically appended linear alkyl-alkynyl chains with terminal amino/guanidino groups improved allosteric effects at both human and mouse A₃ARs. The chain length, functionality, and attachment position were varied to modulate A₃AR PAM activity. For example, 26 (MRS8247, p-alkyne-linked 8 methylenes) and homologues increased agonist Cl-IB-MECA's E_max and potency ([³⁵S]GTPγS binding). The putative mechanism involves a flexible, terminally cationic chain penetrating the lipid environment for stable electrostatic anchoring to cytosolic phospholipid head groups, suggesting "lipid trolling", supported by molecular dynamic simulation of the active-state model. Thus, we have improved A₃AR PAM activity through rational design based on an extrahelical, lipidic binding site.

Author List

Pradhan B, Pavan M, Fisher CL, Salmaso V, Wan TC, Keyes RF, Rollison N, Suresh RR, Kumar TS, Gao ZG, Smith BC, Auchampach JA, Jacobson KA

Authors

John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Robert Keyes PhD Research Scientist II in the Biochemistry department at Medical College of Wisconsin
Brian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin
Tina C. Wan PhD Research Scientist II in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenosine A3 Receptor Agonists
Allosteric Regulation
Allosteric Site
Animals
CHO Cells
Cricetulus
Humans
Lipids
Mice
Quinolines
Receptor, Adenosine A3
Structure-Activity Relationship