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Cryo-EM studies located its extrahelical binding site on TMs 5 and 6, and extensive empirical SAR is consistent with the experimental A\n                    <jats:sub>1<\/jats:sub>\n                    AR structure. At the anti-inflammatory A\n                    <jats:sub>3<\/jats:sub>\n                    AR, a series of 1\n                    <jats:italic>H<\/jats:italic>\n                    -imidazo[4,5-\n                    <jats:italic>c<\/jats:italic>\n                    ]quinolin-4-amine PAMs, originally derived from an A\n                    <jats:sub>1<\/jats:sub>\n                    AR antagonist scaffold, was recently found, using mutagenesis and molecular modeling, to bind at an extrahelical, lipid-exposed site on the receptor. The\n                    <jats:italic>N<\/jats:italic>\n                    4 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 A\n                    <jats:sub>3<\/jats:sub>\n                    AR 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.\n                    <jats:italic>N<\/jats:italic>\n                    1 alkylation with benzyl groups removed residual A\n                    <jats:sub>3<\/jats:sub>\n                    AR antagonism and produced substantial enhancement of agonist potency as well as E\n                    <jats:sub>max<\/jats:sub>\n                    . Both A\n                    <jats:sub>1<\/jats:sub>\n                    AR and A\n                    <jats:sub>3<\/jats:sub>\n                    AR 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.\n                  <\/jats:p>","DOI":"10.1007\/s00044-026-03534-5","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T10:48:58Z","timestamp":1773658138000},"page":"1821-1838","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["From empirical screening to lipid trolling: the evolution of extrahelical allosteric modulators of A1 and A3 adenosine receptors"],"prefix":"10.1007","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6234-5934","authenticated-orcid":false,"given":"Matteo","family":"Pavan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6597-192X","authenticated-orcid":false,"given":"Siva Hariprasad","family":"Kurma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9148-931X","authenticated-orcid":false,"given":"Paola","family":"Oliva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7621-8136","authenticated-orcid":false,"given":"David P.","family":"Broughton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhan-Guo","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8005-4599","authenticated-orcid":false,"given":"John A.","family":"Auchampach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8104-1493","authenticated-orcid":false,"given":"Kenneth A.","family":"Jacobson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"3534_CR1","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1124\/pharmrev.121.000445","volume":"74","author":"AP IJzerman","year":"2022","unstructured":"IJzerman AP, Jacobson KA, M\u00fcller CE, Cronstein BN, Cunha RA. 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