An early GPCR positive allosteric modulator (PAM) was the 2-amino-3-benzoylthiophene derivative PD81,723, which enhances G i -coupled A 1 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 A 1 AR structure. At the anti-inflammatory A 3 AR, a series of 1 H -imidazo[4,5- c ]quinolin-4-amine PAMs, originally...