{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T09:07:04Z","timestamp":1784624824266,"version":"3.55.0"},"reference-count":31,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Heart, Lung, and Blood of the National Institutes of Health","award":["R01 HL133501"],"award-info":[{"award-number":["R01 HL133501"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Membranes"],"abstract":"<jats:p>G protein-coupled receptors (GPCRs) are among the most common drug targets, with numerous agonists and antagonists approved for clinical use. More recently, it has been appreciated that drugs can also modulate the action of natural agonists of these receptors, thus providing unique clinical advantages. Here, we describe the identification and characterization of a small molecule positive allosteric modulator (PAM) of secretin action at the class B G protein-coupled secretin receptor. This phenyl(trifluoromethyl)-pyrimidine can occupy the secretin receptor without stimulating its internalization, yet priming it to enhance both the potency and efficacy of the action of natural secretin. This is also shown to exhibit its effects on cells expressing low numbers of these receptors, without enhancing the effects of other structurally related hormones acting at other class B GPCRs. The mechanism responsible for this PAM effect is the slowing of the off-rate of receptor-bound secretin. This compound can serve as a lead to the development of other drugs that enhance the action of natural endogenous secretin and can be utilized to explore the potential therapeutic utility of such compounds.<\/jats:p>","DOI":"10.3390\/membranes16070249","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T08:14:27Z","timestamp":1784621667000},"page":"249","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification and Characterization of a Phenyl(trifluoro-methyl)-pyrimidine Positive Allosteric Modulator of the Secretin Receptor"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0411-5334","authenticated-orcid":false,"given":"Kaleeckal G.","family":"Harikumar","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ 85259, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela G.","family":"Dengler","sequence":"additional","affiliation":[{"name":"Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leire","family":"Borrega Roman","sequence":"additional","affiliation":[{"name":"Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Ardecky","sequence":"additional","affiliation":[{"name":"Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduard A.","family":"Sergienko","sequence":"additional","affiliation":[{"name":"Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4554-3872","authenticated-orcid":false,"given":"Laurence J.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ 85259, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1196\/annals.1317.013","article-title":"Secretin: A pleiotrophic hormone","volume":"1070","author":"Chu","year":"2006","journal-title":"Ann. 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