Novel, flexible, and conformationally defined analogs of gepirone: synthesis and 5-HT1A, 5-HT2A, and D2 receptor activity

Novel, flexible arylpiperazine gepirone analogs (1a-3a) with a mixed 5-HT1A/5-HT2A receptor profile, low D2 receptor affinity, and agonistic (2a) or partial agonistic (1a, 3a) activity toward 5-HT1A receptor sites were synthesized. Their conformationally restricted counterparts (1b-3b) were selective 5-HT1A ligands (over 5-HT2A and D2 receptors), which turned out to be agonists (2b, 3b), or partial agonist (1b) of 5-HT1A receptors.     

Evaluation of Poly(2-Ethyl-2-Oxazoline) Containing Copolymer Networks of Varied Composition as Sustained Metoprolol Tartrate Delivery Systems

Segmented copolymer networks (SCN) based on poly(2-ethyl-2-oxazoline) and containing 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, and/or methyl methacrylate segments have been evaluated as potential sustained release systems of the water soluble cardioselective β-blocker metoprolol tartrate. The structure and properties of the drug carriers were investigated by differential scanning calorimetry, attenuated total reflectance Fourier transform infrared spectroscopy, scanning electron microscopy, and atomic force microscopy. Swelling kinetics of SCNs in various media was followed, and the conditions for effective MT loading were specified. MT-loaded SCNs with drug content up to 80 wt.% were produced. The release kinetics of metoprolol tartrate from the systems was studied and it was shown that the conetworks of different structure and composition are able to sustain the metoprolol tartrate release without additional excipients.     

The influence of substitution at aromatic part of 1,2,3,4-tetrahydroisoquinoline on in vitro and in vivo 5-HT(1A)/5-HT(2A) receptor activities of its 1-adamantoyloaminoalkyl derivatives.

Further structure-activity relationship (SAR) studies with the 1,2,3,4-tetrahydroisoquinoline (THIQ) class of 5-HT(1A) ligands led to the synthesis of new 1-adamantoyloaminoalkyl derivatives. The impact of substituent variations in the aromatic part of THIQ moiety on 5-HT(1A) and 5-HT(2A) receptor affinities, as well as in vivo functional properties of the investigated compounds were discussed. It was found that those modifications reduced the binding affinity for 5-HT(1A) receptors (in comparison with unsubstituted THIQ derivatives); however, the majority of new compounds still remained potent 5-HT(1A) ligands (K(i)=4.9-46 nM) and most of them showed features of partial agonists of postsynaptic 5-HT(1A) receptors. At the same time, their 5-HT(2A) receptor affinity was slightly increased (K(i)=40-1475 nM), which resulted in a loss of 5-HT(2A)/5-HT(1A) selectivity. 5-Br,8-OCH3 derivative-the most potent, mixed 5-HT(1A)/5-HT(2A) ligand-produced activation of presynaptic 5-HT(1A) receptors and showed properties of a 5-HT(2A) receptor antagonist.     

Synthesis and pharmacological evaluation of new arylpiperazines. 3-[4-[4-(3-chlorophenyl)-1-piperazinyl]butyl]-quinazolidin-4-one - a dual serotonin 5-HT(1A)/5-HT(2A) receptor ligand with an anxiolytic-like activity

On the basis of systematic studies on the structure–activity relationships in arylpiperazine group of serotonin ligands, 12 new derivatives containing quinazolidin-4(3H)-one (1–4), 2-phenyl-2,3-dihydrophthalazine-1,4-dione (5–8) or 1-phenyl-1,2-dihydropyridazine-3,6-dione (9–12) fragments were synthesized. The majority of the tested compounds (2, 4, 7, 8 and 10–12) showed a high affinity for 5-HT_1A receptors (K_i=11–54 nM) and two (1, 2) were found active at 5-HT_2A sites (16 and 68 nM, respectively). All the new 5-HT_1A ligands tested in vivo revealed an antagonistic activity at postsynaptic 5-HT_1A receptors, and three of them behaved as agonists at presynaptic ones. Additionally, both the meta-chlorophenylpiperazine derivatives containing quinazolidin-4-one fragment showed features of 5-HT_2A receptor antagonists. The dual 5-HT_1A/5-HT_2A receptor ligand (2) was further tested for its potential psychotropic activity. It showed a distinct anxiolytic-like activity in a conflict drinking test in rats and the observed effect was more potent in terms of the active dose, than that produced by diazepam (used as a reference drug).     

Comparison of Manual and Automated Preprocedural Segmentation Tools to Predict the Annulus Plane Angulation and C-Arm Positioning for Transcatheter Aortic Valve Replacement

BackgroundPreprocedural manual multi-slice-CT-segmentation tools (MSCT-ST) define the gold standard for planning transcatheter aortic valve replacement (TAVR). They are able to predict the perpendicular line of the aortic annulus (PPL) and to indicate the corresponding C-arm angulation (CAA). Fully automated planning-tools and their clinical relevance have not been systematically evaluated in a real world setting so far.ConclusionsA-MSCT-analysis provides precise preprocedural information on CAA for optimal visualization of the aortic annulus compared to the M-MSCT gold standard. Intraprocedural application of this information during TAVR significantly reduces the levels of contrast and radiation exposure.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01805739","term_id":"NCT01805739"}}NCT01805739     

Portals, blogs and co.: the role of the Internet as a medium of science communication

While the use of the Internet for the exchange of scientific data was characterised by exclusivity during its pioneer era, the active employment of the medium today, by a broad social spectrum of users in the exchange of information, for dialogue and in the accumulation of knowledge, displays an almost unbounded inclusion. Blo and online encyclopaedias based on the 'Wikipedia' model have contributed to the formation of a marketplace in which the free expression of opinions and the relaying of information occur. Counted among the ideas which have been popularised in the wake of this phenomenon, "lay journalism" and the "wisdom of the masses" are seen to be integral to the new 'web 2.0'. Consequently, the ever-increasing information disseminated in the web has been diluted in quality and authenticity, resulting in the presentation of new challenges to online science journalism. In reference to the public debate surrounding green gene technology, the communications platform bioSicherheit.de, which receives more than one million visitors per year, will be examined as an example of an agent that retrieves and mobilises information on biological safety research and that successfully has established itself as an intermediary between the scientific community and the broader public.     

Estradiol effect on indomethacin and prostaglandin E2-modulation of adrenergic transmission in rabbit oviduct.

The effect of prostaglandin E2 /PGE2/ and indomethacin on 3H-noradrenaline (3H-NA) release- and on contractions-evoked by field electrical stimulation (FES) was studied in vitro in oviductal isthmus of mature rabbits (untreated and treated with estradiol). FES evoked guanethidine-sensitive contractions and calcium-dependent tritium overflow, which reflected 3H-NA overflow. Marked and concentration-dependent decrease of FES-evoked contractions by PGE2 (0.1-100 nM) was observed in both groups of animals. The inhibitory effect of PGE2 was more pronounced in estradiol treated animals (IC50 1.5 nM, n = 9) than in untreated animals (IC50 18 nM, n = 6). Indomethacin, 1 microM, induced a remarkably pronounced increase of FES-evoked contractions in estradiol treated (by 57.3 +/- 6.3%, n = 8) in comparison with untreated rabbits (21.4 +/- 3.8%, n = 7). The amount of FES-evoked release of tritium was significantly higher in untreated than in estradiol treated rabbits. PGE2 decreased and indomethacin increased tritium-evoked release. The effects of PGE2 and indomethacin on tritium-evoked release showed no estradiol dependence. The competitive results of PGE2 and indomethacin on both evoked contraction and 3H-NA release suggest that endogenous prostaglandin E2 takes part in modulation of adrenergic mediated contraction and that estradiol enhanced the prostaglandin effect.