Fluorescent H2 Receptor Squaramide-Type Antagonists: Synthesis, Characterization, and Applications.

Fluorescence labeled ligands have been gaining importance as molecular tools, enabling receptor-ligand-binding studies by various fluorescence-based techniques. Aiming at red-emitting fluorescent ligands for the hH2R, a series of squaramides labeled with pyridinium or cyanine fluorophores (19-27) was synthesized and characterized. The highest hH2R affinities in radioligand competition binding assays were obtained in the case of pyridinium labeled antagonists 19-21 (pK i: 7.71-7.76) and cyanine labeled antagonists 23 and 25 (pK i: 7.67, 7.11). These fluorescent ligands proved to be useful tools for binding studies (saturation and competition binding as well as kinetic experiments), using confocal microscopy, flow cytometry, and high content imaging. Saturation binding experiments revealed pK d values comparable to the pK i values. The fluorescent probes 21, 23, and 25 could be used to localize H2 receptors in HEK cells and to determine the binding affinities of unlabeled compounds.

Cost evaluation of an innovative outreach clinic across social insurance codes in rural Northern Germany - A routine data analysis.

A community outreach clinic was established in 2013 in a rural part of Germany to counsel and better integrate patients with mental health disorders or clients with psychosocial problems into the healthcare and complementary social assistance system. In a pilot study, we aimed to evaluate the costs of the integration assistance system after the outreach clinic was opened, the number of visits and the trend in the costs of the social assistance system of the federal state. Anonymised secondary cost data were used to evaluate the costs associated with the integration assistance receivers before (2010-2012) and after the establishment of the outreach clinic (2013-2015). Total costs were descriptively compared between the intervention group (consultation in the outreach clinic), the non-referral group, and a propensity score-matched control group for the years 2013-2015. To monitor the counselling activity, we used anonymised data on visits to the outreach clinic between 2013 and 2015. Data from 50 clients in the outreach clinic and 678 non-referral clients were analysed. The total costs of the integration assistance for the years 2013-2015 amounted to EUR 21,516 (95% CI 14,513-28,518) and EUR 28,464 (25,789-31,140) respectively. Propensity score matching of the controls resulted in equalised total costs for the years 2013 through 2015 for clients (n = 50, EUR 21,516 (14,513-28,518)) and controls (n = 250, EUR 21,725 (18,214-25,234)). The total number of integration assistance receivers in the district was lower than the average for the federal state. The number of consultations at the outpatient clinic steadily increased from 146 in 2013 to 1,090 in 2015. Counselling in the outreach clinic might help reduce the placement of clients into integration assistance, including supported housing, and slow the expected cost trend. However, counselling failed to lower total costs in the integration assistance service, possibly due to the selection of more severe cases.

Descriptive Cost-Effectiveness Analysis of a Counseling and Coordination Model in Psychosocial Care. Integration of Health Care and Social Rehabilitation.

INTRODUCTION: A psychosocial outreach clinic was established to offer counseling and coordination of healthcare and complementary services for persons with psychosocial and mental problems. The cost-effectiveness of these services was measured based on a pre-post comparison. METHODS: A prospective observational study was conducted with clients of the outreach clinic. Data on resource consumption and quality of life were collected at baseline and follow-up after 3, 6, and 12 months using the Client Sociodemographic and Service Receipt Inventory to assess service utilization, and the 12-Item Short Form Health Survey to assess quality of life. The objective of the present analysis was to estimate the relation between monetary expenditure and QALYs (quality-adjusted life-years), before and after the outreach clinic was established, descriptively. The analysis was constructed from payer's perspective and was supplemented by a sensitivity analysis. RESULTS: A total of 85 participants were included. Total annual expenditures before the intervention were 5,832 € per client for all service segments. During the 12-months study duration expenditures decreased to 4,350 € including the costs associated with outreach clinic services. QALYs for the 12-month study period were 0.6618 and increased about 0.0568 compared to the period before. DISCUSSION: Despite methodological limitations due to small sample size, a pre-post comparison and the retrospective cost data collection, this study suggests acceptability of the outreach clinic as cost-effective. CONCLUSION: The activities of the outreach clinic as an integrated care model seem to be cost-effective regarding the relation between monetary expenditures and clients' quality of life.

[(3) H]UR-DE257: development of a tritium-labeled squaramide-type selective histamine H2 receptor antagonist.

A series of new piperidinomethylphenoxypropylamine-type histamine H2 receptor (H2 R) antagonists with different substituted "urea equivalents" was synthesized and characterized in functional in vitro assays. Based on these data as selection criteria, radiosynthesis of N-[6-(3,4-dioxo-2-{3-[3-(piperidin-1-ylmethyl)phenoxy]propylamino}cyclobut-1-enylamino)hexyl]-(2,3-(3) H2 )propionic amide ([(3) H]UR-DE257) was performed. The radioligand (specific activity: 63 Ci mmol(-1) ) had high affinity for human, rat, and guinea pig H2 R (hH2 R, Sf9 cells: Kd , saturation binding: 31 nM, kinetic studies: 20 nM). UR-DE257 revealed high H2 R selectivity on membranes of Sf9 cells, expressing the respective hHx R subtype (Ki values: hH1 R: >10000 nM, hH2 R: 28 nM, hH3 R: 3800 nM, hH4 R: >10000 nM). In spite of insurmountable antagonism, probably due to rebinding of [(3) H]UR-DE257 to the H2 R (extended residence time), the title compound proved to be a valuable pharmacological tool for the determination of H2 R affinities in competition binding assays.

Red-fluorescent argininamide-type NPY Y1 receptor antagonists as pharmacological tools.

Fluorescently labelled NPY Y(1) receptor (Y(1)R) ligands were synthesized by connecting pyrylium and cyanine dyes with the argininamide-type Y(1)R antagonist core structure by linkers, covering a wide variety in length and chemical nature, attached to the guanidine group. The most promising fluorescent probes had Y(1)R affinities (radioligand binding) and antagonistic activities (calcium assay) in the one- to two-digit nanomolar range. These compounds turned out to be stable under assay conditions and to be appropriate for the detection of Y(1)Rs by confocal microscopy in live cells. To improve the signal-to-noise ratio by shifting the emission into the near infrared, a new benzothiazolium-type fluorescent cyanine dye (UR-DE99) was synthesized and attached to the parent antagonist via a carbamoyl linker yielding UR-MK131, a highly potent fluorescent Y(1)R probe, which was also successfully applied in flow cytometry.