{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T22:36:00Z","timestamp":1776465360478,"version":"3.51.2"},"reference-count":17,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T00:00:00Z","timestamp":1642118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["P30GM122733"],"award-info":[{"award-number":["P30GM122733"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Modulation of the endocannabinoid system (ECS) is of great interest for its therapeutic relevance in several pathophysiological processes. The CB2 subtype is largely localized to immune effectors, including microglia within the central nervous system, where it promotes anti-inflammation. Recently, a rational drug design toward precise modulation of the CB2 active site revealed the novelty of Pyrrolo[2,1-c][1,4]benzodiazepines tricyclic chemotype with a high conformational similarity in comparison to the existing leads. These compounds are structurally unique, confirming their chemotype novelty. In our continuing search for new chemotypes as selective CB2 regulatory molecules, following SAR approaches, a total of 17 selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs were synthesized and tested for their ability to bind to the CB1 and CB2 receptor orthosteric sites. A competitive [3H]CP-55,940 binding screen revealed five compounds that exhibited &gt;60% displacement at 10 \u03bcM concentration. Further concentration-response analysis revealed two compounds, 4k and 4q, as potent and selective CB2 ligands with sub-micromolar activities (Ki = 146 nM and 137 nM, respectively). In order to support the potential efficacy and safety of the analogs, the oral and intravenous pharmacokinetic properties of compound 4k were sought. Compound 4k was orally bioavailable, reaching maximum brain concentrations of 602 \u00b1 162 ng\/g (p.o.) with an elimination half-life of 22.9 \u00b1 3.73 h. Whether administered via the oral or intravenous route, the elimination half-lives ranged between 9.3 and 16.7 h in the liver and kidneys. These compounds represent novel chemotypes, which can be further optimized for improved affinity and selectivity toward the CB2 receptor.<\/jats:p>","DOI":"10.3390\/molecules27020509","type":"journal-article","created":{"date-parts":[[2022,1,16]],"date-time":"2022-01-16T20:45:21Z","timestamp":1642365921000},"page":"509","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Identification of an Orally Bioavailable, Brain-Penetrant Compound with Selectivity for the Cannabinoid Type 2 Receptor"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9592-0138","authenticated-orcid":false,"given":"Meirambek","family":"Ospanov","sequence":"first","affiliation":[{"name":"National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677, USA"},{"name":"Department of Chemistry and Technology of Organic Substances, Natural Compounds and Polymers, Al-Farabi Kazakh National University, al-Farabi Ave. 71, Almaty 050040, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0665-9757","authenticated-orcid":false,"given":"Suresh P.","family":"Sulochana","sequence":"additional","affiliation":[{"name":"Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5628-1134","authenticated-orcid":false,"given":"Jason J.","family":"Paris","sequence":"additional","affiliation":[{"name":"Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John M.","family":"Rimoldi","sequence":"additional","affiliation":[{"name":"Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Ashpole","sequence":"additional","affiliation":[{"name":"Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larry","family":"Walker","sequence":"additional","affiliation":[{"name":"National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3807-1299","authenticated-orcid":false,"given":"Samir A.","family":"Ross","sequence":"additional","affiliation":[{"name":"National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677, USA"},{"name":"Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3192-4233","authenticated-orcid":false,"given":"Abbas G.","family":"Shilabin","sequence":"additional","affiliation":[{"name":"Department of Chemistry, East Tennessee State University, Johnson City, TN 37614, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0257-860X","authenticated-orcid":false,"given":"Mohamed A.","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.it.2008.05.002","article-title":"Why neurodegenerative diseases are progressive: Uncontrolled inflammation drives disease progression","volume":"29","author":"Gao","year":"2008","journal-title":"Trends Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/nrn3887","article-title":"Spreading of pathology in neurodegenerative diseases: A focus on human studies","volume":"16","author":"Brettschneider","year":"2015","journal-title":"Nat. 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