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1	First in Class (S,E)-11-[2-(Arylmethylene)Hydrazono]-PBD Analogs as Selective CB2 Modulators Targeting Neurodegenerative Disorders Mingle, David, Ospanov, Meirambek, Radwan, Mohamed O., Ashpole, Nicole, Otsuka, Masami, Ross, Samir A., Walker, Larry A., Shilabin, Abbas G., Ibrahim, Mohamed A. 01 January 2021 (has links) Newly designed pyrrolo[2,1-c][1,4]benzodiazepines tricyclic skeleton has shown potential clusters of cannabinoid receptors CB1/CB2 selective ligands. CB2 plays a critical role in microglial-derived neuroinflammation, where it modulates cell proliferation, migration, and differentiation into M1 or M2 phenotypes. Beginning with computer-based docking studies accounting the recently discovered X-ray crystal structure of CB2, we designed a series of PBD analogs as potential ligands of CB2 and tested their binding affinities. Interestingly, computational studies and theoretical binding affinities of several selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs, have revealed the presence of potential selectivity in binding attraction toward CB1 and CB2. Reported here is the discovery of the first representatives of this series of selective binding to CB2. Preliminary data showed that this class of molecules display potential binding efficacy toward the cannabinoid receptors tested. Intriguingly, initial cannabinoid binding assay showed a selective binding affinity of 4g and 4h showed Ki of 0.49 and 4.7 μM toward CB2 receptors while no binding was observed to CB1. The designed leads have shown remarkable stability pattern at the physiological pH magnifying their therapeutic values. We hypothesize that the PBD tricyclic structure offers the molecule an appropriate three-dimensional conformation to fit snugly within the active site of CB2 receptors, giving them superiority over the reported CB2 agonists/inverse agonists. Our findings suggested that the attachment of heterocyclic ring through the condensation of diazepine hydrazone and S- or N-heterocyclic aldehydes enhances the selectivity of CB2 over CB1. [Figure not available: see fulltext.]. Cannabinoid receptors CB1/CB2 Central nervous system (CNS) neurodegenerative diseases neuroinflammation pyrrolobenzodiazepines
2	Identification of an Orally Bioavailable, Brain-Penetrant Compound with Selectivity for the Cannabinoid Type 2 Receptor Ospanov, Meirambek, Sulochana, Suresh P., Paris, Jason J., Rimoldi, John M., Ashpole, Nicole, Walker, Larry, Ross, Samir A., Shilabin, Abbas G., Ibrahim, Mohamed A. 14 January 2022 (has links) 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 [H]CP-55,940 binding screen revealed five compounds that exhibited >60% displacement at 10 μM concentration. Further concentration-response analysis revealed two compounds, and , as potent and selective CB2 ligands with sub-micromolar activities ( = 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 were sought. Compound 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. administration oral animals chemistry) binding sites brain (metabolism) drug design endocannabinoids (metabolism) kidney (metabolism) ligands liver (metabolism) male mice models molecular pyrroles (administration & dosage chemistry) receptors cannabinoid (chemistry metabolism) structure-activity relationship cannabinoid receptors CB1/CB2 central nervous system (CNS) neurodegenerative diseases neuroinflammation pharmacokinetics (PK) pyrrolobenzodiazepines radioligand binding assay Chemistry

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First in Class (S,E)-11-[2-(Arylmethylene)Hydrazono]-PBD Analogs as Selective CB2 Modulators Targeting Neurodegenerative Disorders

Identification of an Orally Bioavailable, Brain-Penetrant Compound with Selectivity for the Cannabinoid Type 2 Receptor