A series of substituted phosphonate derivatives were designed and synthesized in order to study the ability of these compounds to inhibit the neuropeptidase N-acetylated alpha-linked acidic dipeptidase (NAALADase). The molecules were shown to act as inhibitors of the enzyme, with the most potent (compound 3) having a Ki of 0.275 nM. The potency of this compound is more than 1000 times greater than that of previously reported inhibitors of the enzyme. NAALADase is responsible for the catabolism of the abundant neuropeptide N-acetyl-aspartylglutamate (NAAG) into N-acetylaspartate and glutamate. NAAG has been proposed to be a neurotransmitter at a subpopulation of glutamate receptors; alternatively, NAAG has been suggested to act as a storage form of synaptic glutamate. As a result, inhibition of NAALADase may show utility as a therapeutic intervention in diseases in which altered levels of glutamate are thought to be involved.
Purpose: The Tufts Center for the Study of Drug Development (CSDD) and the Drug Information Association (DIA) in collaboration with 8 pharmaceutical and biotechnology companies conducted a study examining the adoption and effect of artificial intelligence (AI), such as machine learning, on drug development. The study was conducted to clarify and understand AI adoption across the industry and to gather detailed insights into the spectrum of activities included in the definition of AI. The study investigated and identified analytical platforms and innovations across pharmaceutical and biotechnology companies currently being used or planned for in the future.Methods: A 2-part method was used that comprised in-depth interviews with AI industry experts and a global survey conducted across pharmaceutical and biotechnology organizations. Eleven in-depth interviews focused on use and implementation of AI across drug development. The survey assessed use of AI and included perceptions about current and future use. The survey also examined technology definitions, assessment of organizational and personal AI expertise, and use of partnerships. A total of 402 responses, including data from 217 unique organizations, were analyzed.Findings: Although 7 in 10 respondents reported using AI in some capacity, a wide range of use was reported by AI type. Patient selection and recruitment for clinical studies was the most commonly reported AI activity, with 34 respondents currently using AI for this activity. In addition, identification of medicinal products data gathering was the top activity being piloted or in the planning stages, reported by 49 respondents. The study also revealed that the most significant challenges to AI implementation included staff skills (55%), data structure (52%), and budgets (49%). Nearly 60% of respondents noted planned increases in staff within 1e2 years to support AI use or implementation.Implications: Despite the challenges to AI implementation, the survey revealed that most organizations use AI in some capacity and that it is important to the success of an organization's workforce. Many organizations reported expectations for increasing staff as implementation of AI expands. Further research should examine the changing development landscape as the role of AI evolves.
In the lateral striatum of aged rats, dopamine D-2 receptor density is reduced and glutamate tissue content is elevated. D-2 receptor agonists have been shown to inhibit stimulated glutamate release. In the present study, microdialysis was used to investigate a potential role for D-2 receptors in the modulation of striatal glutamate efflux from 4-, 12-, 18-, and 24-26-month-old Fischer 344 rats. Extracellular basal glutamate concentrations significantly increased as a function of age in the lateral, but not medial, striatum. Neither the D-2 agonist, LY 163502, nor the D-2 antagonist, sulpiride, influenced basal glutamate efflux, suggesting that the dopaminergic system is not involved in the observed age-related increase in extracellular basal glutamate levels. In contrast to basal efflux, potassium-evoked glutamate release was not altered with age. However, LY 163502 significantly inhibited stimulated glutamate release in 4-month-old rats. This inhibitory action was not observed at any other age. Sulpiride alone did not alter stimulated glutamate release, but it did block the inhibitory effect of LY 163502 in the 4-month-old rats. These results provide in vivo evidence for an age-related functional loss in the modulation of striatal glutamate release by dopamine D-2 receptors in addition to increased basal glutamate efflux, which is not related to D-2 receptor modulation. Such mechanisms could be important in the pathophysiology of striatal cell death during aging and age-related neurodegenerative diseases.
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