{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:11:10Z","timestamp":1792789870235,"version":"4.5.0"},"reference-count":47,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"NSF","doi-asserted-by":"publisher","award":["CHE 2101221"],"award-info":[{"award-number":["CHE 2101221"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"award":["CHE 2101221"],"award-info":[{"award-number":["CHE 2101221"]}],"id":[{"id":"https:\/\/ror.org\/021nxhr62","id-type":"ROR","asserted-by":"publisher"}]},{"name":"NIH","award":["R01-DA042157"],"award-info":[{"award-number":["R01-DA042157"]}]},{"award":["R01-DA042157"],"award-info":[{"award-number":["R01-DA042157"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Campbell University","id":[{"id":"https:\/\/ror.org\/00dv9q566","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00dv9q566","id-type":"ROR","asserted-by":"publisher"}]},{"name":"NIGMS","award":["K12-GM102773"],"award-info":[{"award-number":["K12-GM102773"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"crossref"}]},{"award":["K12-GM102773"],"award-info":[{"award-number":["K12-GM102773"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006545","name":"NIMHD","doi-asserted-by":"publisher","award":["P20-MD002303"],"award-info":[{"award-number":["P20-MD002303"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"publisher"}]},{"award":["P20-MD002303"],"award-info":[{"award-number":["P20-MD002303"]}],"id":[{"id":"https:\/\/ror.org\/0493hgw16","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Diphenylpyraline analogs JKH1 and JKH10 are monoamine transporter inhibitors and promote relaxation in mouse mesenteric arteries. Here, we evaluated JKH1 and JKH for their interaction with CB1 cannabinoid receptor signaling. In N18TG2 mouse neuroblastoma cells that endogenously express CB1 receptors, JKH1 and JKH10 stimulated [35S]GTP\u03b3S binding in a concentration-dependent manner; this stimulation was non-competitively antagonized by the CB1 antagonist-inverse agonist SR141716 (1 \u00b5M). JKH10 (but not JKH1) inhibited forskolin-stimulated cAMP accumulation with efficacy as high as the full orthosteric agonist WIN55212-2, and this Gi-mediated inhibition was completely precluded by pertussis toxin treatment. However, JKH1 was a poor inhibitor. The SR141716 failed to completely block the inhibition by JKH10. Both JKH analogs stimulated ERK phosphorylation, but inhibition by SR141716 (1 \u00b5M) did not appear to be overcome by increasing concentrations of JKH1 or JKH10. In mouse isolated mesenteric arteries, both analogs (1 \u00b5M) attenuated the contractile response, but only the response to JKH10 was blocked by the CB1 antagonist-inverse agonist O-2050 (1 \u00b5M). Docking studies to protein data bank CB1 structures 7FEE and 6KQI showed JKH1 was predicted to dock predominantly at a pregnenolone-binding site, whereas JKH10 was predicted to dock at both the pregnenolone and a cholesterol consensus motif at helices 2\u20133\u20134 inner membrane leaflet. Thus, a series of diphenylpyraline derivatives can behave as CB1 receptor stimulators, and in silico evidence supports that this could result from interaction with cholesterol and\/or pregnenolone protein surface binding sites rather than the orthosteric binding site.<\/jats:p>","DOI":"10.3390\/molecules31203699","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T13:35:29Z","timestamp":1792071329000},"page":"3699","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diphenylpyraline Derivatives Are Allosteric Agonists of the CB1 Cannabinoid Receptor"],"prefix":"10.3390","volume":"31","author":[{"given":"Khalil","family":"Eldeeb","sequence":"first","affiliation":[{"name":"Jerry M. 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