RESUMEN

The P2X3 receptor (P2X3R), an ATP-gated cation channel predominantly expressed in C- and Aδ-primary afferent neurons, has been proposed as a drug target for neurological inflammatory diseases, e.g., neuropathic pain, and chronic cough. Aiming to develop novel, selective P2X3R antagonists, tetrazolopyrimidine-based hit compound 9 was optimized through structure-activity relationship studies by modifying the tetrazole core as well as side chain substituents. The optimized antagonist 26a, featuring a cyclopropane-substituted triazolopyrimidine core, displayed potent P2X3R-antagonistic activity (IC50 = 54.9 nM), 20-fold selectivity versus the heteromeric P2X2/3R, and high selectivity versus other P2XR subtypes. Noncompetitive P2X3R blockade was experimentally confirmed by calcium influx assays. Cryo-electron microscopy revealed that 26a stabilizes the P2X3R in its desensitized state, acting as a molecular barrier to prevent ions from accessing the central pore. In vivo studies in a rat neuropathic pain model (spinal nerve ligation) showed dose-dependent antiallodynic effects of 26a, thus presenting a novel, promising lead structure.

Asunto(s)

Microscopía por Crioelectrón , Antagonistas del Receptor Purinérgico P2X , Pirimidinas , Receptores Purinérgicos P2X3 , Triazoles , Animales , Antagonistas del Receptor Purinérgico P2X/farmacología , Antagonistas del Receptor Purinérgico P2X/química , Antagonistas del Receptor Purinérgico P2X/síntesis química , Relación Estructura-Actividad , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Ratas , Receptores Purinérgicos P2X3/metabolismo , Humanos , Triazoles/farmacología , Triazoles/química , Triazoles/síntesis química , Sitio Alostérico , Masculino , Neuralgia/tratamiento farmacológico , Descubrimiento de Drogas , Ratas Sprague-Dawley

RESUMEN

IMPORTANCE: Autistic youth who graduate with a high school diploma may experience challenges in acquiring functional skills for everyday independence. Few studies have focused on how their functional and self-management skills change during the transition to adulthood. OBJECTIVE: To examine cross-sectional differences and longitudinal changes in the functional and self-management skills of transition-age autistic youth. DESIGN: Exploratory longitudinal study (18-mo follow-up). SETTING: Community. PARTICIPANTS: Autistic high school students who graduated with a high school diploma and their parents (N = 50). OUTCOMES AND MEASURES: Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (ASD). RESULTS: Older youth (ages 18-20 yr) had significantly lower normative Social/Cognitive and Responsibility domain scores (i.e., self-management) than youth ages 14-17 yr. Approximately 2 yr later, youth in both age groups significantly improved in scaled scores on the Daily Activities and Responsibility domains. CONCLUSIONS AND RELEVANCE: Autistic youth's functional and self-management skills fell below those of nonautistic peers; however, these skills do change over time and are therefore appropriate targets for intervention. Plain-Language Summary: The findings of this study highlight the importance of focusing on the functional and self-management skills of autistic youth as part of their transition to adulthood. Occupational therapists can play a valuable role in helping autistic youth to achieve independence as adults by assessing their functional needs and strengths and by providing client-centered interventions.

Asunto(s)

Actividades Cotidianas , Humanos , Adolescente , Masculino , Femenino , Adulto Joven , Estudios Longitudinales , Estudios Transversales , Automanejo , Trastorno Autístico/rehabilitación , Factores de Edad , Terapia Ocupacional/métodos

RESUMEN

Background: Despite high rates of obesity and weight-related conditions observed in children with Down syndrome, little is known about how to prevent these conditions. Purpose: The purpose of this study was to identify parent-perceived facilitators and barriers to health for toddlers (12-36 months old) with Down syndrome. Materials and methods: We conducted in-depth, semi-structured interviews with the mothers of 25 toddlers with Down syndrome. All interviews were conducted using Zoom Video Technology, audio recorded and transcribed before being coded in NVivo software using a structured protocol. Thematic analysis was used to identify themes in perceived facilitators and barriers to health at the level of the child, family, and community. Data were triangulated using reflective journaling, video review of child meals, and member-checking techniques. Results: We identified unique themes for facilitators (on the move and sound sleep) and barriers (co-occurring conditions and eating behaviors) at the level of the child. At the level of the family and community, overarching themes that were viewed as either a facilitator or barrier, depending on the context, were identified (role models matter, time is critical, the importance of place, and social support). Conclusion: These themes can help clinicians and researchers tailor their health promotion interventions to meet the unique needs of children with Down syndrome by using strength-based approaches and providing families with the tools to overcome barriers.

RESUMEN

P2X3 receptors (P2X3R) are ATP-gated ion channels predominantly expressed in C- and Aδ-fiber primary afferent neurons and have been introduced as a novel therapeutic target for neurological disorders, including neuropathic pain and chronic cough. Because of its localized distribution, antagonism of P2X3R has been thoroughly considered, and the avoidance of issues related to CNS side effects has been proven in clinical trials. In this article, benzimidazole-4,7-dione-based derivatives were introduced as a new chemical entity for the development of P2X3R antagonists. Starting from the discovery of a hit compound from the screening of 8364 random library compounds in the Korea Chemical Bank, which had an IC50 value of 1030 nM, studies of structure-activity and structure-property relationships enabled further optimization toward improving the antagonistic activities as well as the drug's physicochemical properties, including metabolic stability. As for the results, the final optimized compound 14h was developed with an IC50 value of 375 nM at P2X3R with more than 23-fold selectivity versus P2X2/3R, along with properties of metabolic stability and improved solubility. In neuropathic pain animal models evoked by either nerve ligation or chemotherapeutics in male Sprague-Dawley rats, compound 14h showed anti-nociceptive effects through an increase in the mechanical withdrawal threshold as measured by von Frey filament following intravenous administration.

Asunto(s)

Analgésicos/química , Analgésicos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Antagonistas del Receptor Purinérgico P2X/química , Antagonistas del Receptor Purinérgico P2X/farmacología , Analgésicos/síntesis química , Animales , Bencimidazoles/síntesis química , Técnicas de Química Sintética , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Monitoreo de Drogas , Humanos , Ratones , Estructura Molecular , Antagonistas del Receptor Purinérgico P2X/síntesis química , Ratas , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad

RESUMEN

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of anti-cancer drugs. Neurotensin receptors (NTSRs) are widely distributed within the pain circuits in the central nervous system. The purpose of this study was to determine the role of NTSR1 by examining the effects of an NTSR1 agonist in rats with CIPN and investigate the contribution of spinal serotonin receptors to the antinociceptive effect. METHODS: Sprague-Dawley rats (weight 150-180 g) were used in this study. CIPN was induced by injecting cisplatin (2 mg/kg) once a day for 4 days. Intrathecal catheters were placed into the subarachnoid space of the CIPN rats. The antiallodynic effects of intrathecally or intraperitoneally administered PD 149163, an NTSR1 agonist, were evaluated. Furthermore, the levels of serotonin in the spinal cord were measured by high-performance liquid chromatography. RESULTS: Intrathecal or intraperitoneal PD 149163 increased the paw withdrawal threshold in CIPN rats. Intrathecal administration of the NTSR1 antagonist SR 48692 suppressed the antinociceptive effect of PD 149163 given via the intrathecal route, but not the antinociceptive effect of intraperitoneally administered PD 149163. Intrathecal administration of dihydroergocristine, a serotonin receptor antagonist, suppressed the antinociceptive effect of intrathecally administered, but not intraperitoneally administered, PD 149163. Injecting cisplatin diminished the serotonin level in the spinal cord, but intrathecal or intraperitoneal administration of PD 149163 did not affect this reduction. CONCLUSIONS: NTSR1 played a critical role in modulating CIPN-related pain. Therefore, NTSR1 agonists may be useful therapeutic agents to treat CIPN. In addition, spinal serotonin receptors may be indirectly involved in the effect of NTSR1 agonist.