Progress in synthesis, modification, characterization and applications of hyperbranched polyphosphate polyesters.

Hyperbranched polyphosphate polyesters (HPPs) as a special class of hyperbranched polymers have attracted increased interest and have been intensively studied, because of peculiar structures, excellent biocompatibility, flexibility in physicochemical properties, biodegradability, water soluble, thermal stability, and mechanical properties. HPPs can be divided into phosphates as monomers and phosphates as end groups. In this article, the classification, general synthesis, modifications, and applications of HPP are reviewed.

Synthesis and biological evaluation of a new class of multi-target heterocycle piperazine derivatives as potential antipsychotics.

In this study, we designed and synthesized a novel series of multi-receptor ligands as polypharmacological antipsychotic agents by using a multi-receptor affinity strategy. Among them, 3w combines a multi-receptor mechanism with high mixed affinities for D, 5-HT, 5-HT and H receptors, and low efficacy at the off-target receptors (5-HT, H and α receptor) and human ether-à-go-go-related gene (hERG) channel. In addition, compound 3w exhibits favorable antipsychotic drug-like activities in assessment.

Discovery of a new class of multi-target heterocycle piperidine derivatives as potential antipsychotics with pro-cognitive effect.

A series of benzoisoxazoleylpiperidine derivatives were synthesized by using the multi-target strategies and their potent affinities for dopamine (DA), serotonin (5-HT) and human histamine H receptors have been evaluated. Of these compounds, the promising candidate 4w displayed high affinities for D, D, 5-HT, 5-HT and H, a moderate affinity for 5-HT, negligible effects on the human ether-a-go-go-related gene (hERG) channel, low affinities for off-target receptors (5-HT, adrenergic α and H). In addition, the animal behavioral study revealed that, compared to risperidone, compound 4w significantly inhibited apomorphine-induced climbing and MK-801-induced movement behaviors with a high threshold for catalepsy and low liabilities for weight gain and hyperprolactinemia.

Design, Synthesis and Biological Investigation of Flavone Derivatives as Potential Multi-Receptor Atypical Antipsychotics.

The design of a series of novel flavone derivatives was synthesized as potential broad-spectrum antipsychotics by using multi-receptor affinity strategy between dopamine receptors and serotonin receptors. Among them, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin- 1-yl) butoxy)-2,2-dimethylchroman-4-one () exhibited a promising preclinical profile. Compound not only showed high affinity for dopamine D, D, and serotonin 5-HT, 5-HT receptors, but was also endowed with low to moderate activities on 5-HT, α, and H receptors, indicating a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation.

Isoquinolinone derivatives as potent CNS multi-receptor D/5-HT/5-HT/5-HT/5-HT agents: Synthesis and pharmacological evaluation.

In this study, a series of novel Isoquinolinone derivatives were synthesized as potential multi-target antipsychotics. Among these, compound 13 showed high affinity for dopamine D and serotonin 5-HT, 5-HT, 5-HT, and 5-HT receptors, showed low affinity for off-target receptors (5-HT, H, and α), and negligible effects on ether-a-gogo-related gene (hERG; i.e.

Synthesis and pharmacological evaluation of piperidine (piperazine)-amide substituted derivatives as multi-target antipsychotics.

We report the optimisation of a series of novel amide-piperidine (piperazine) derivatives using the multiple ligand approach with dopamine and serotonin receptors. Of the derivatives, compound 11 exhibited high affinity for the D, 5-HT, and 5-HT receptors, but low affinity for the 5-HT and histamine H receptors and human ether-a-go-go-related gene (hERG) channels. In vivo, compound 11 reduced apomorphine-induced climbing, MK-801-induced hyperactivity and DOI-induced head twitching without observable catalepsy, even at the highest dose tested.

Polymorphs and pharmacokinetics of an antipsychotic drug candidate.

A potent antipsychotic drug candidate, 7-(4-(4-(6-fluorobenzo[d]-isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro -2H-chromen-2-one mesylate(CY611), with good in vitro and in vivo antipsychotic effects was investigated for preformulation evaluation by crystallography methods. Three anhydrous polymorphs(Form I-III), a monohydrate(Form IV), and a NMP solvate(Form V) were discovered and characterized by powder X-ray diffraction, thermal analysis, attenuated total reflection-fourier transform infrared spectroscopy and scanning electron microscopy. Form I, monohydrate Form IV, and a NMP solvate Form V of the drug candidate were isolated, and their structures were determined by single crystal X-ray diffraction.

Polymorphs of DP-VPA Solid Solutions and Their Physicochemical Properties.

Different solid forms possess various physicochemical properties, which can significantly affect the stability, bioavailability, and manufacturability of the final product. DP-VPA, a complex of 1-stearoyl-2-valproyl-sn-glycero-3-phosphatidylcholine (DP-VPA-C) and 1-palmitoyl-2-valproyl-sn-glycero-3-phosphatidylcholine (DP-VPA-C), is currently under development as an antiepileptic drug. DP-VPA-C and DP-VPA-C crystallize together in solid solution forms.

Piperidine propionamide as a scaffold for potent sigma-1 receptor antagonists and mu opioid receptor agonists for treating neuropathic pain.

We designed and synthesized a novel series of piperidine propionamide derivatives as potent sigma-1 (σ) receptor antagonists and mu (μ) opioid receptor agonists, and measured their affinity for σ and μ receptors in vitro through binding assays. The basic scaffold of the new compounds contained a 4-substituted piperidine ring and N-aryl propionamide. Compound 44, N-(2-(4-(4-fluorobenzyl) piperidin-1-yl) ethyl)-N-(4-methoxy-phenyl) propionamide, showed the highest affinity for σ receptor (K σ = 1.