Identification of an Orally Bioavailable, Brain-Penetrant Compound with Selectivity for the Cannabinoid Type 2 Receptor
Ospanov M. Sulochana S.P. Paris J.J. Rimoldi J.M. Ashpole N. Walker L. Ross S.A. Shilabin A.G. Ibrahim M.A.
January-2 2022MDPI
Molecules
2022#27Issue 2
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 chemo-type 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 >60% displace-ment at 10 µM 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 ± 162 ng/g (p.o.) with an elimination half-life of 22.9 ± 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.
Cannabinoid receptors CB1/CB2 , Central nervous system (CNS) , Neurode-generative diseases , Neuroinflammation , Pharmacokinetics (PK) , Pyrrolobenzodiazepines , Radioligand binding assay
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National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, 38677, MS, United States
Department of Chemistry and Technology of Organic Substances, Natural Compounds and Polymers, Al-Farabi Kazakh National University, al-Farabi Ave. 71, Almaty, 050040, Kazakhstan
Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, 38677, MS, United States
Department of Chemistry, East Tennessee State University, Johnson City, 37614, TN, United States
National Center for Natural Products Research
Department of Chemistry and Technology of Organic Substances
Department of BioMolecular Sciences
Department of Chemistry
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