Structural Optimization of the Diarylurea PSNCBAM-1, an Allosteric Modulator of Cannabinoid Receptor 1.
• PSNCBAM-1 is an allosteric modulator of the cannabinoid receptor 1. • Derivatives of PSNCBAM-1 were made, to reduce the total rings in the structure. • Several derivatives maintained allosteric activity, as shown by binding experiments. • Some calculated physicochemical properties for these deriva...
| Publicado en: | Current Therapeutic Research Vol. 92 |
|---|---|
| Autores principales: | , , , |
| Formato: | research tables/charts Journal Article |
| Publicado: |
Elsevier B.V.
2020
|
| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=144690106&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 144690106 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 0011393X KIH jtl: Current Therapeutic Research issn: 0011393X maglogo: N pubinfo: dt: 2020 vid: 92 pid: 467 pub: Elsevier B.V. place: New York, New York artinfo: ui: 144690106 144690106 144690106 10.1016/j.curtheres.2019.100574 144690106 ppct: 1 formats: tig: atl: Structural Optimization of the Diarylurea PSNCBAM-1, an Allosteric Modulator of Cannabinoid Receptor 1. aug: au: Dopart, Rachel Immadi, Sri Sujana Lu, Dai Kendall, Debra A. affil: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut sug: subj: Urea Analysis Cannabinoids Analysis Pyridines Analysis Receptors, Cell Surface Analysis Urea Antagonists and Inhibitors Cannabinoids Antagonists and Inhibitors Pyridines Antagonists and Inhibitors Receptors, Cell Surface Antagonists and Inhibitors Human Molecular Structure Piperidines Analysis Solubility Bioinformatics Computer Simulation Methods Biochemical Phenomena ab: • PSNCBAM-1 is an allosteric modulator of the cannabinoid receptor 1. • Derivatives of PSNCBAM-1 were made, to reduce the total rings in the structure. • Several derivatives maintained allosteric activity, as shown by binding experiments. • Some calculated physicochemical properties for these derivatives are provided. Structure–activity relationship studies improve the pharmacological and pharmacokinetic properties of a lead compound such as PSNCBAM-1, an allosteric modulator of the cannabinoid receptor 1. Here, several derivatives of PSNCBAM-1 were synthesized with the aim of reducing the number of rings within its structure and enhancing the solubility of the compounds. The derivatives studied contain substituents previously shown to enhance binding of agonists (ie, a cyano group and a pyrimidine ring), with a reduced number of rings compared with the parent compound, PSNCBAM-1. The synthesized compounds were tested for the enhancement of the binding of orthosteric cannabinoid receptor 1 agonist CP55,940 in the presence of varying concentrations of each test compound. Select compounds were also tested for their effects on cannabinoid receptor 1 inverse agonist SR141716A binding. The compounds were also subjected to computational analysis of drug-like properties and solubility. Consistent with a positive allosteric modulator for orthosteric ligand binding, compounds LDK1317 (12a), LDK1320 (12b), LDK1321 (6a), LDK1323 (8a), and LDK1324 (6b) all enhanced the binding of agonist CP55,940 to some degree. Reduction in the number of rings did not abolish the activity. The new lead compounds LDK1317 (12a) and LDK1321 (6a) showed improved drug-like properties and enhanced solubility in silico. In contrast to PSNCBAM-1, the synthesized compounds are analogs with fewer rings. The compounds LDK1317 (12a) and LDK1321 (6a) contained only 2 or 3 rings, respectively, and showed the binding parameters (K B = 110 nM, α = 2.3, and K B = 85 nM, α = 5.9). Further, the computationally predicted drug-like properties and solubility suggest these compounds are acceptable new lead compounds for further development of cannabinoid receptor 1 allosteric modulators. (Curr Ther Res Clin Exp. 2020; 81:XXX–XXX) pubtype: Academic Journal doctype: research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
|---|