94682-46-9Relevant academic research and scientific papers
Phase behaviour analysis of solid dispersions of loperamide and two structurally related compounds with the polymers PVP-K30 and PVP-VA64
Weuts, Ilse,Kempen, Dieter,Decorte, Annelies,Verreck, Geert,Peeters, Jef,Brewster, Marcus,Van Den Mooter, Guy
, p. 375 - 385 (2004)
The purpose of the present study was to investigate the influence of the structure of a poorly water soluble model drug (loperamide) on the phase behaviour in solid dispersions with PVP-K30. Dispersions with PVP-VA64, a less hydrophilic polymer, were investigated as well in order to study the influence of differences in polymer structure and water content of the samples. The solid dispersions of PVP-K30 or PVP-VA64 with loperamide as well as with two fragments of this molecule were prepared by spray drying. The amount of residual solvents and water was determined with GC and thermogravimetric analysis (TGA). The drug loading of the dispersions was determined using high performance liquid chromatography (HPLC). The solid state properties were evaluated using powder-XRD, IR-spectroscopy and MT-DSC. All mixtures containing loperamide proved to be completely amorphous, whereas the dispersions containing the fragments are only amorphous in case the polymer content is high. The phase diagrams that were constructed clearly show that loperamide exhibits a different behaviour in the solid dispersions than its two building blocks. They also point to the presence of specific intermolecular compound-polymer interactions in the dispersions of one of the fragments with the two polymers. This was confirmed by the IR-results. Despite structural similarities, interactions in dispersions containing loperamide are far less important. In dispersions containing high concentrations of the other fragment, the DSC curves give indications for polymorphism whereas IR and XRD-spectra point towards inclusion of solvent in these samples.
Novel Dual-Target μ-Opioid Receptor and Dopamine D3Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management
Bonifazi, Alessandro,Battiti, Francisco O.,Sanchez, Julie,Zaidi, Saheem A.,Bow, Eric,Makarova, Mariia,Cao, Jianjing,Shaik, Anver Basha,Sulima, Agnieszka,Rice, Kenner C.,Katritch, Vsevolod,Canals, Meritxell,Lane, J. Robert,Newman, Amy Hauck
, p. 7778 - 7808 (2021/06/27)
The need for safer pain-management therapies with decreased abuse liability inspired a novel drug design that retains μ-opioid receptor (MOR)-mediated analgesia, while minimizing addictive liability. We recently demonstrated that targeting the dopamine D3 receptor (D3R) with highly selective antagonists/partial agonists can reduce opioid self-administration and reinstatement to drug seeking in rodent models without diminishing antinociceptive effects. The identification of the D3R as a target for the treatment of opioid use disorders prompted the idea of generating a class of ligands presenting bitopic or bivalent structures, allowing the dual-target binding of the MOR and D3R. Structure-activity relationship studies using computationally aided drug design and in vitro binding assays led to the identification of potent dual-target leads (23, 28, and 40), based on different structural templates and scaffolds, with moderate (sub-micromolar) to high (low nanomolar/sub-nanomolar) binding affinities. Bioluminescence resonance energy transfer-based functional studies revealed MOR agonist-D3R antagonist/partial agonist efficacies that suggest potential for maintaining analgesia with reduced opioid-abuse liability.
