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1	Characterization of the binding of the novel compound GT-002 to GABAA receptors in the mammalian brain : Development and validation of a radioligand binding assay. A comparative study to Flumazenil Emelie, Zemowska January 2017 (has links) Gamma-Amino butyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian central nervous system (CNS) and inhibits the neurotransmission by targeting the ionotropic transmembrane GABAA receptor. Modulators of the GABAA receptor targets the allosteric binding sites and modifies the GABA effect and these sites acts as superior drug targets within psychopharmacology. Gabather AB has developed the novel compound GT-002 that is known to target the receptor and cause a behavioral effect in rodents. This project characterized the binding of the lead compound GT-002 to GABAA receptor in mammalian brain tissue by development and validation of a radioligand binding assay. In the assay a comparative evaluation was performed using the benzodiazepine (BZ) antagonist Flumazenil (FLU). All experiments were performed using GABAA receptors originating from porcine and mouse brain tissue membrane, where no significant difference between the mammals was displayed. GT-002 binds with higher affinity and associates faster than FLU to the receptor and implies a two-binding site model. GT-002 displaced FLU and no tested competitive analytes targeting various modulatory sites of the receptor displaced GT-002, implying independent binding of GT-002 and allosterically impacts the BZ binding site. GABAA receptor Radioligand binding assay GT-002 Triazoloquinazolinedione Flumazenil Neuropharmacology Medical and Health Sciences Medicin och hälsovetenskap
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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Characterization of the binding of the novel compound GT-002 to GABAA receptors in the mammalian brain : Development and validation of a radioligand binding assay. A comparative study to Flumazenil

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