Med Chem Res. 2026 Mar 16. doi: 10.1007/s00044-026-03534-5. Online ahead of print.
ABSTRACT
An early GPCR positive allosteric modulator (PAM) was the 2-amino-3-benzoylthiophene derivative PD81,723, which enhances G-coupled A adenosine receptor (AR) agonist effects. Cryo-EM studies located its extrahelical binding site on TMs 5 and 6, and extensive empirical SAR is consistent with the experimental AAR structure. At the anti-inflammatory AAR, a series of 1H-imidazo[4,5-c]quinolin-4-amine PAMs, originally derived from an AAR antagonist scaffold, was recently found, using mutagenesis and molecular modeling, to bind at an extrahelical, lipid-exposed site on the receptor. The N4 and C2 positions on the scaffold were modified with substituted phenyl and cycloalkyl/branched alkyl groups, respectively, as in the prototypical PAM LUF6000. Before the structural binding hypothesis, extensive synthetic optimization failed to introduce hydrophilic groups needed for aqueous compatibility. Eventually, secondary anchoring of these AAR PAMs within the phospholipid bilayer (lipid trolling) succeeded in improving the pharmacological profile, based on the attraction of appended terminal cationic chains on the PAM with anionic phospholipid head groups. Molecular dynamics (MD) simulation has predicted a rearrangement of anionic lipids around H8 when long-amino chain PAMs bind, and an upward movement of H8 that is reported to be associated with Class A GPCR activation. N1 alkylation with benzyl groups removed residual AAR antagonism and produced substantial enhancement of agonist potency as well as E. Both AAR and AAR PAMs can activate partially in the absence of orthosteric agonist. Thus, at both receptors, potent PAMs have been discovered and optimized for selective enhancement of endogenous adenosine and potentially for treatment of conditions such as chronic pain. Collectively, extrahelical, lipid-exposed pockets are druggable allosteric sites in Class A GPCRs and amenable to deliberate engagement of the membrane environment to optimize receptor modulation. The evolution from empirical screening to structure-guided and membrane-aware design provides a generalizable framework for targeting signaling across the GPCR superfamily beyond ARs.
PMID:42446533 | DOI:10.1007/s00044-026-03534-5