Design and synthesis of orally-active and selective azaindane 5HT2c agonist for the treatment of obesity.

Based on our original pyrazine hit, CP-0809101, novel conformationally-restricted 5HT2c receptor agonists with 2-piperazin-azaindane scaffold were designed. Synthesis and structure-activity relationship (SAR) studies are described with emphasis on optimization of the selectivity against 5HT2a and 5HT2b receptors with excellent 2c potency. Orally-active and selective compounds were identified with dose-responsive in vivo efficacy in our pre-clinical food intake model.

Orally active and brain permeable proline amides as highly selective 5HT2c agonists for the treatment of obesity.

Brain-penetrable proline amides were developed as 5HT2c agonists with more than 1000-fold binding selectivity against 5HT2b receptor. After medicinal chemistry optimization and SAR studies, orally active proline amides with robust efficacy in a rodent food intake inhibition model were uncovered.

Design, synthesis, and pharmacology of fluorescently labeled analogs of serotonin: application to screening of the 5-HT2C receptor.

Novel fluorescent derivatives of serotonin have been synthesized and used as tracers for the development of a 5-HT2C fluorescence polarization assay. Serotonin analogs that feature a fluorescent probe attached through an ether linkage at the tryptamine 5-position have high affinity for the 5-HT2C receptor, and affinity is dependent on both linker length and pendent dye. These variables have been optimized to generate Cy3B derivative 5a, which has 10-fold higher 5-HT2C affinity relative to serotonin (Kd=0.23 nM). In receptor activation experiments, 5a acts as a full agonist of 5-HT2C. Upon binding to 5-HT2C cell membranes, 5a shows a robust increase in fluorescence polarization (FP) signal. In an FP binding assay using 5a as a tracer ligand, Ki values for known 5-HT2C agonists and antagonists showed excellent agreement with Ki values from radioligand binding (r2=0.93). The FP ligand assay is suitable for high-throughput drug screening applications with respect to speed of analysis, displaceable signal, precision, and sensitivity to various reagents. A 384-well-based high-throughput assay that is rapid, economical, and predictive of test compounds' ability to bind to the 5-HT2C receptor has been compiled and validated.

Corporate social responsibility initiatives addressing social exclusion in Bangladesh.

The private sector is often seen as a driver of exclusionary processes rather than a partner in improving the health and welfare of socially-excluded populations. However, private-sector initiatives and partnerships- collectively labelled corporate social responsibility (CSR) initiatives-may be able to positively impact social status, earning potential, and access to services and resources for socially-excluded populations. This paper presents case studies of CSR projects in Bangladesh that are designed to reduce social exclusion among marginalized populations and explores whether CSR initiatives can increase economic and social capabilities to reduce exclusion. The examples provide snapshots of projects that (a) increase job-skills and employment opportunities for women, disabled women, and rehabilitated drug-users and (b) provide healthcare services to female workers and their communities. The CSR case studies cover a limited number of people but characteristics and practices replicable and scaleable across different industries, countries, and populations are identified. Common success factors from the case studies form the basis for recommendations to design and implement more CSR initiatives targeting socially-excluded groups. The analysis found that CSR has potential for positive and lasting impact on developing countries, especifically on socially-excluded populations. However, there is a need for additional monitoring and critical evaluation.

Micro-insurance in Bangladesh: risk protection for the poor?

Health services and modem medicines are out of reach for over one billion people globally. Micro-insurance for health is one method to address unmet health needs. This case study used a social exclusion perspective to assess the health and poverty impact of micro-insurance for health in Bangladesh and contrasts this with several micro-insurance systems for health offered in India. Micro-insurance for health in Bangladesh targeted towards the poor and the ultra-poor provides basic healthcare at an affordable rate whereas the Indian micro-insurance schemes for health have been implemented across larger populations and include high-cost and low-frequency events. Results of analysis of the existing literature showed that micro-insurance for health as currently offered in Bangladesh increased access to, and use of, basic health services among excluded populations but did not reduce the likelihood that essential health-related costs would be a catastrophic expense for a marginalized household.