Adherence to Complication Reporting for Randomized Controlled Trials Contained in Clinical Practice Guidelines for the Management of Carpal Tunnel Syndrome.

Purpose: Randomized controlled trials (RCTs) are frequently used in creating recommendations contained within clinical practice guidelines (CPGs). However, investigations outside of hand surgery have reported that RCTs within CPGs infrequently report complications and harms-related data. Our purpose was to assess adherence to complication reporting and harms-related outcomes contained in the Consolidated Standards for Reporting (CONSORT) Extension of Harms and Standards for Reporting of Diagnostic Accuracy Studies (STARD) reporting checklists for RCTs within the American Academy of Orthopaedic Surgery (AAOS) CPGs for carpal tunnel syndrome (CTS). Methods: We identified all RCTs within the AAOS CTS CPGs. All therapeutic RCTs and diagnostic studies were included. We used the CONSORT Harms Checklist criteria to assess adherence to the reporting of adverse events for therapeutic RCTs and the STARD criteria to assess the diagnostic accuracy of the articles. We defined adequate compliance as adherence to ≥50% of the checklist items. Results: We identified 82 therapeutic RCTs and 90 diagnostic accuracy articles within the AAOS CTS CPG. For therapeutic RCTs, we found that the average compliance with the published checklists was 19%. For diagnostic studies, the average compliance with checklists was found to be 55%. Eleven therapeutic RCTs (13%) and 60 diagnostic studies (67%) were determined to have adequate compliance for the CONSORT and STARD checklists, respectively. Conclusions: Randomized controlled trials in the AAOS CPGs for CTS have low compliance with the CONSORT Extension for Harms Checklist. Although the overall adherence to the items published in the STARD statement for diagnostic accuracy evaluation remains higher, future efforts should be made to improve the adherence rates to both checklists. Clinical relevance: Improved standardization of complication reporting may aid in comparing outcomes across multiple clinical investigations of upper-extremity procedures.

Structure-Activity Relationship of Truncated 2,8-Disubstituted-Adenosine Derivatives as Dual A2A/A3 Adenosine Receptor Antagonists and Their Cancer Immunotherapeutic Activity.

Based on hA2AAR structures, a hydrophobic C8-heteroaromatic ring in 5'-truncated adenosine analogues occupies the subpocket tightly, converting hA2AAR agonists into antagonists while maintaining affinity toward hA3AR. The final compounds of 2,8-disubstituted-N6-substituted 4'-thionucleosides, or 4'-oxo, were synthesized from d-mannose and d-erythrono-1,4-lactone, respectively, using a Pd-catalyst-controlled regioselective cross-coupling reaction. All tested compounds completely antagonized hA2AAR, including 5d with the highest affinity (Ki,A2A = 7.7 ± 0.5 nM). The hA2AAR-5d X-ray structure revealed that C8-heteroaromatic rings prevented receptor activation-associated conformational changes. However, the C8-substituted compounds still antagonized hA3AR. Structural SAR features and docking studies supported different binding modes at A2AAR and A3AR, elucidating pharmacophores for receptor activation and selectivity. Favorable pharmacokinetics were demonstrated, in which 5d displayed high oral absorption, moderate half-life, and bioavailability. Also, 5d significantly improved the antitumor effect of anti-PD-L1 in vivo. Overall, this study suggests that the novel dual A2AAR/A3AR nucleoside antagonists would be promising drug candidates for immune-oncology.

An Analysis of Formal Patient Complaints, Risk, and Malpractice Events Involving Orthopedic Trauma Surgeons During a 10-Year Period.

Formal patient complaints and malpractice events involving orthopedic trauma surgeons (OTSs) can have substantial career implications. Our purpose was to analyze formal patient complaints, risk events, and malpractice events against OTSs during a 10-year period. We reviewed all formal patient complaints within our institution's patient advocacy database involving 9 fellowship-trained OTSs throughout a decade. Complaints were categorized using the Patient Complaint Analysis System. Potential risk and malpractice events involving the OTSs were recorded. A control group of all patients seen by the surgeons during the study period was created. Demographics between patients with complaints and the control group were analyzed, as were malpractice, risk, and complaint rates between the surgeons. Of 33,770 patients, 136 filed a formal complaint (0.40%). There were 29 malpractice claims and 2 malpractice lawsuits. The care and treatment domain accounted for the highest percentage of complaints (36%), followed by the access and availability domain (26%). Results of the logistic regression analysis indicated that private insurance (odds ratio, 1.58) and operative treatment (odds ratio, 3.65) were significantly associated with complaints. Despite statistically significant differences in the rates of complaint and risk events between surgeons, malpractice events did not differ. The rate of patient complaints within a large orthopedic trauma practice during a 10-year period was 0.40%. Patients with private insurance and those treated operatively were more likely to file a complaint. Whereas complaint rates among surgeons varied, there was no significant difference in the rate of malpractice events. Understanding patient complaint rates and categorizations may allow surgeons to target areas for improvement. [Orthopedics. 2023;46(2):121-127.].

Intraoperative Conversion From Endoscopic to Open Carpal Tunnel Release: A Systematic Review and Case Series.

PURPOSE: The purpose of this study was to assess the incidence, outcomes, and complications associated with conversion from endoscopic carpal tunnel release (ECTR) to open carpal tunnel release (OCTR). METHODS: A retrospective case review of all patients who underwent ECTR over 4 years by 2 fellowship-trained hand surgeons at a single academic center was performed. We recorded outcomes and the reason for conversion in patients who underwent conversion to an OCTR. Baseline demographics and surgical complications were compared between the 2 groups. A systematic review was performed to define the incidence and reasons for conversion from ECTR to OCTR. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we included clinical studies of ECTR from 2000 to 2021. RESULTS: In the retrospective series, 9 of 892 (1.02%) ECTR cases underwent conversion to an OCTR at the time of the index procedure. One of 9 converted cases had transient neurapraxia involving the recurrent motor branch after surgery compared with 0 cases in the group that underwent ECTR without conversion. Improvements in the visual analog scale for pain and QuickDASH were noted at a mean of 46 weeks after surgery in the group that underwent conversion to OCTR. The systematic review identified an incidence of conversion of 0.62%. The most common reasons for conversion to OCTR in the case series and systematic review were poor visualization due to hypertrophic tenosynovium and aberrant nerve anatomy. CONCLUSIONS: The overall incidence of intraoperative conversion from ECTR to OCTR during the index procedure was 1.02%, with the most common reasons for conversion being poor visualization due to hypertrophic tenosynovium and aberrant nerve anatomy. Patients who undergo conversion from ECTR to OCTR demonstrate improvements in pain and disability, similar to patients who undergo ECTR without conversion. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Novel alendronate-CGS21680 conjugate reduces bone resorption and induces new bone formation in post-menopausal osteoporosis and inflammatory osteolysis mouse models.

Loss of bone is a common medical problem and, while it can be treated with available therapies, some of these therapies have critical side effects. We have previously demonstrated that CGS21680, a selective A2A adenosine receptor agonist, prevents bone loss, but its on-target toxicities (hypotension, tachycardia) and frequent dosing requirements make it unusable in the clinic. We therefore generated a novel alendronate-CGS21680 conjugate (MRS7216), to target the agonist to bone where it remains for long periods thereby diminishing the frequency of administration and curtailing side effects. MRS7216 was synthesized from CGS21680 by sequential activation of the carboxylic acid moiety and reacting with an appropriate amino acid (PEG, alendronic acid) under basic conditions. MRS7216 was tested on C57BL/6J (WT) mice with established osteoporosis (OP) and WT or A2A KO mice with wear particle-induced inflammatory osteolysis (OL). Mice were treated weekly with MRS7216 (10mg/kg). Bone formation was studied after in vivo labeling with calcein/Alizarin Red, and µCT and histology analyses were performed. In addition, human primary osteoblasts and osteoclasts were cultured using bone marrow discarded after hip replacement. Receptor binding studies demonstrate that MRS7216 efficiently binds the A2A adenosine receptor. MRS7216-treated OP and OL mice had significant new bone formation and reduced bone loss compared to vehicle or alendronate-treated mice. Histological analysis showed that MRS7216 treatment significantly reduced osteoclast number and increased osteoblast number in murine models. Interestingly, cultured human osteoclast differentiation was inhibited, and osteoblast differentiation was stimulated by the compound indicating that MRS7216 conjugates represent a novel therapeutic approach to treat osteoporosis and osteolysis.

Trends in the Management of Fifth Metacarpal Neck Fractures.

PURPOSE: To describe management trends of fifth metacarpal neck (5MCN) fractures within a large health care system. We aimed to define patient and surgeon factors associated with nonsurgical versus surgical treatment, as well as to identify factors associated with receiving care only in the emergency department (ED). METHODS: We identified all 5MCN fractures within our system for the years 2012-2020 and recorded baseline demographics for cases. Injury, treatment, and fracture characteristics were all recorded. For fractures treated nonsurgically, we determined the type of immobilization used (if any) and recorded whether patients were seen only in the ED or received subsequent outpatient follow-up. Demographic comparisons were made between groups, and adjusted logistic regression models were generated to predict the odds of having a surgical 5MCN fracture or being seen in the ED only. RESULTS: There were 611 5MCN fractures over an 8-year period, of which 10% were treated surgically. During the first half of the study period, 8% of isolated cases were treated surgically compared with 7% of cases in the second half. Soft dressings were increasingly used. There were no nonsurgically managed cases that underwent subsequent surgical procedures for symptomatic nonunion or malunion. Twenty-one percent of patients were seen only in the ED. Fracture angulation, associated injuries, insurance status, and treatment by a hand surgeon were all significantly associated with an increased likelihood of surgery. CONCLUSIONS: Of the 611 5MCN fractures identified, 90% were treated nonsurgically. Patient and surgeon factors were associated with increased odds of surgery. Of patients who sought care for 5MCN injuries, >20% received no follow-up care outside of the ED. These data can be used to assess future changes in management trends and suggest that nonunion and symptomatic malunions are uncommon occurrences. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

The Effect of Salary Compensation for Time Spent Teaching in an Orthopaedic Residency Program: An Analysis of Teaching Performance Reviews.

INTRODUCTION: Although there has been a recent emphasis on standardized resident assessments within Accrediation Council for Graduate Medical Education programs, assessments of faculty teaching performance and effectiveness are less frequent. Our purpose was to compare the teaching performance of orthopaedic surgery faculty receiving compensation for time spent teaching with faculty without compensation. METHODS: For this prospective investigation, we collected anonymous resident reviews of 23 orthopaedic faculty within a rural, academic orthopaedic residency program over 2 academic years. Performance reviews of the faculty used a validated assessment of clinical teaching effectiveness with nine domains (faculty knowledge, organization, enthusiasm, rapport, involvement in learning experiences, feedback, clinical skill, accessibility, and overall effectiveness). A composite teaching effectiveness score was determined by adding each of the scores from the individual domains. We compared reviews for faculty members with and without compensation for time spent teaching. RESULTS: A total of 202 performance reviews for 23 orthopaedic faculty were analyzed. Most of the faculty were male (91%), and 61% received compensation for teaching. No demographic differences were observed between the two faculty groups. Notable differences between the groups were noted in three domains: enthusiasm, ability to establish rapport as well as direction, and feedback. Faculty compensated for teaching demonstrated a markedly higher composite teaching effectiveness score than those without compensation. DISCUSSION: These data suggest that orthopaedic faculty compensated for teaching responsibilities provide a better educational experience for resident trainees compared with faculty without compensation for teaching. Future studies should aim to assess varying compensation models for teaching responsibilities across different departments.

Prophylactic Antibiotics Prior to Hand Surgery in Patients with Prosthetic Joints.

Background: To determine the prevalence of prosthetic joint infections (PJIs) after elective clean hand surgery in order to determine whether prophylactic antibiotics are warranted in patients who have previously undergone total joint arthroplasty (TJA). Methods: All patients undergoing elective clean hand surgery between 2012 and 2018 were retrospectively cross-referenced with patients who had previously undergone a TJA at the same urban academic medical center. Inclusion criteria were any patients who underwent clean hand surgery during the study period who were an adult between the ages of 30 and 90, had a previous TJA, and did not have a previous history of a PJI. All charts were reviewed to collect data on patient demographics, co-morbidities, the type of TJA and hand surgery performed, whether prophylactic antibiotics were used prior to the hand surgery, and whether a PJI occurred within 3 months of the hand surgery. Results: Total of 331 patients (181 females and 150 males) were identified over the 6-year period that met inclusion criteria. In total, 13% of the patients received prophylactic antibiotics prior to their hand surgery and 87% had not. Only 1 case of a PJI occurred within 3 months of a hand surgery. No relationship was identified between the PJI and the hand surgery, nor the need for preoperative antibiotic prophylaxis. Conclusions: Incidence of PJI after clean hand surgery is very low. We do not recommend the routine use of antibiotic prophylaxis in patients undergoing clean elective hand surgery with a history of prior TJA in order to prophylax against a PJI.

Analysis of the Most Frequently Cited Articles in Hand and Wrist Surgery: A Modern Reading List.

The aim of this investigation was to analyze the 50 most frequently cited articles on hand and wrist surgery of all time and those published during the 21st century. We aimed to evaluate the article, author, and journal characteristics for these publications in order to create a modern reading list of impactful upper-extremity articles. A search of the Journal Citation Reports 2022 edition to identify journals containing possible hand or wrist-related articles was performed. Related journals were identified and then searched on the Web of Science database to identify hand and wrist articles. The top 50 most cited articles overall and the top 50 most cited articles from 2000-2021 were identified and indexed. Several bibliometric parameters, such as study type, study topic, study design, level of evidence, citation count, citation density, the institution of the lead author, the gender of lead and senior authors, and country were analyzed. For the most cited articles of all time, the number of citations ranged from 224 to 1109 with a mean of 368 citations and 15.0 citation density. Citations for the top 50 articles from 2000-2021 ranged from 153 to 950 with a mean of 233 citations and 14.5 citation density. For both groups, the most common level of evidence was level IV (33% and 27%). No correlation between journal impact factor and citation count or citation density was found. In both groups, "fracture" was the most common topic and papers were predominantly written by male authors. Frequently cited publications on hand and wrist surgery are often clinical papers that contain low levels of evidence and tend to focus on topics related to fracture care. Female authors remain underrepresented.

Volar Plating versus Headless Compression Screw Fixation of Scaphoid Nonunions: A Meta-analysis of Outcomes.

Background Headless compression screw fixation with bone grafting has been the mainstay of treatment for scaphoid nonunion for the past several decades. Recently, locked volar plate fixation has gained popularity as a technique for scaphoid fixation, especially for recalcitrant or secondary nonunions. Purpose The purpose of this meta-analysis was to compare union rates and clinical outcomes between locked volar plate fixation and headless compression screw fixation for the treatment of scaphoid nonunions. Methods A literature search was performed for studies documenting treatment outcomes for scaphoid nonunions from 2000 to 2020. Inclusion criteria consisted of (1) average age > 18 years, (2) primary study using screw fixation, plate fixation, or both, with discrete data reported for each procedure, and (3) average follow-up of at least 3 months. Exclusion criteria consisted of studies with incomplete or missing data on union rates. Data from each study was weighted, combined within treatment groups, and compared across treatment groups using a generalized linear model or binomial distribution. Results Following title and full-text review, 23 articles were included for analysis. Preoperatively, patients treated with plate fixation had significantly longer time from injury to surgery and were more likely to have failed prior surgical intervention. There was no significant difference between union rates at 92 and 94% for screw and plate fixation, respectively. However, plate fixation resulted in longer time to union and lower modified Mayo wrist scores. Conclusion Patients treated with locked volar plate fixation were more likely to be used for recalcitrant or secondary nonunions. There was no statistically significant difference in union rates between screw and plate fixation. The results from this meta-analysis support the select use of locked volar plate fixation for scaphoid nonunion, especially recalcitrant nonunions and those that have failed prior surgical repair.

Is Wearable Technology Part of the Future of Orthopedic Health Care?

Wearable technology is an exciting industry that has gained exponential traction over the past few years. This technology allows individuals to track personal health and fitness parameters and is becoming more and more precise with modern advancements. As these devices continue to increase in accuracy and gain further utilities in health monitoring, their potential to influence orthopedic care will also grow. Orthopedic surgeons may use this technology to monitor the perioperative course of their patients, who can remotely communicate various parameters related to care without needing to physically be seen by their providers. Wearable devices, while of course promising in the field of medicine, still have limitations that must be overcome before they can widely be adopted into orthopedic care. Our goal is to review current wearables on the market, discuss their potential applications in health care, and postulate their future use in orthopedic care.

Point-of-care versus central testing of hemoglobin during large volume blood transfusion.

BACKGROUND: Point-of-care (POC) hemoglobin testing has the potential to revolutionize massive transfusion strategies. No prior studies have compared POC and central laboratory testing of hemoglobin in patients undergoing massive transfusions. METHODS: We retrospectively compared the results of our point-of-care hemoglobin test (EPOC®) to our core laboratory complete blood count (CBC) hemoglobin test (Sysmex XE-5000™) in patients undergoing massive transfusion protocols (MTP) for hemorrhage. One hundred seventy paired samples from 90 patients for whom MTP was activated were collected at a single, tertiary care hospital between 10/2011 and 10/2017. Patients had both an EPOC® and CBC hemoglobin performed within 30 min of each other during the MTP. We assessed the accuracy of EPOC® hemoglobin testing using two variables: interchangeability and clinically significant differences from the CBC. The Clinical Laboratory Improvement Amendments (CLIA) proficiency testing criteria defined interchangeability for measurements. Clinically significant differences between the tests were defined by an expert panel. We examined whether these relationships changed as a function of the hemoglobin measured by the EPOC® and specific patient characteristics. RESULTS: Fifty one percent (86 of 170) of paired samples' hemoglobin results had an absolute difference of ≤7 and 73% (124 of 170) fell within ±1 g/dL of each other. The mean difference between EPOC® and CBC hemoglobin had a bias of - 0.268 g/dL (p = 0.002). When the EPOC® hemoglobin was < 7 g/dL, 30% of the hemoglobin values were within ±7, and 57% were within ±1 g/dL. When the measured EPOC® hemoglobin was ≥7 g/dL, 55% of the EPOC® and CBC hemoglobin values were within ±7, and 76% were within ±1 g/dL. EPOC® and CBC hemoglobin values that were within ±1 g/dL varied by patient population: 77% for cardiac surgery, 58% for general surgery, and 72% for non-surgical patients. CONCLUSIONS: The EPOC® device had minor negative bias, was not interchangeable with the CBC hemoglobin, and was less reliable when the EPOC® value was < 7 g/dL. Clinicians must consider speed versus accuracy, and should check a CBC within 30 min as confirmation when the EPOC® hemoglobin is < 7 g/dL until further prospective trials are performed in this population.

Repurposing of a Nucleoside Scaffold from Adenosine Receptor Agonists to Opioid Receptor Antagonists.

While screening off-target effects of rigid (N)-methanocarba-adenosine 5'-methylamides as A3 adenosine receptor (AR) agonists, we discovered µM binding hits at the δ-opioid receptor (DOR) and translocator protein (TSPO). In an effort to increase OR and decrease AR affinity by structure activity analysis of this series, antagonist activity at κ-(K)OR appeared in 5'-esters (ethyl 24 and propyl 30), which retained TSPO interaction (µM). 7-Deaza modification of C2-(arylethynyl)-5'-esters but not 4'-truncation enhanced KOR affinity (MRS7299 28 and 29, K i ≈ 40 nM), revealed µ-OR and DOR binding, and reduced AR affinity. Molecular docking and dynamics simulations located a putative KOR binding mode consistent with the observed affinities, placing C7 in a hydrophobic region. 3-Deaza modification permitted TSPO but not OR binding, and 1-deaza was permissive to both; ribose-restored analogues were inactive at both. Thus, we have repurposed a known AR nucleoside scaffold for OR antagonism, with a detailed hypothesis for KOR recognition.

Patient Adoption and Utilization of a Web-Based and Mobile-Based Portal for Collecting Outcomes After Elective Orthopedic Surgery.

Health care increasingly collects patient-reported outcomes (PROs) via web-based platforms. The purpose of this study was to evaluate how patient age influences portal engagement. Patients undergoing elective surgery at a single multispecialty orthopedic practice from September 2014 to February 2017 had access to an online portal to complete PROs, message the clinic, and view physical therapy instructions. A mobile app was optionally available. Age, sex, log-in frequency, PRO completion rates, and number of messages sent were reviewed retrospectively. Message frequency, log-in rates, and PRO compliance were highest for patients aged 41 to 50, 51 to 60, and 61 to 70, respectively. Mobile app use decreased with age ( P = .002); yet, at all ages, the mobile app group was more engaged. In particular, for patients aged 18 to 30 years, log-in frequency increased 2.5-fold and PRO compliance improved 44% ( P < .001) in the mobile app group. This study demonstrates that portal interaction varies by age and that data capture is highest in patients who choose the mobile app.

Which Domains of the ODI Best Predict Change in Physical Function in Patients After Surgery for Degenerative Lumbar Spondylolisthesis?

STUDY DESIGN: A retrospective review. OBJECTIVE: The purpose of this study is to determine the differential improvement of the various individual items of the Oswestry Disability Index (ODI) and to determine their relationship to other measures of Health Related Quality of Life (HRQOL). SUMMARY OF BACKGROUND DATA: The ODI is an easily scored, common, 10-item questionnaire about symptoms relevant to lumbar spine pathology. It is not clear if all of the items can be reliably applied to spine surgery. The purpose of this study is to determine the differential improvement of the various individual items of the ODI and to determine their relationship to other measures of HRQOL. METHODS: Analysis of a prospective registry of patients treated at an academic medical center was undertaken. At baseline, standardized outcome measures including ODI and SF12 PCS were collected on all patients undergoing elective fusion surgery for degenerative spondylolisthesis. Multiple linear regressions were performed using change in SF12 PCS as the dependent variable and change in ODI components as the independent variables. RESULTS: Baseline and 1-year follow-up data were collected on 196 patients (mean age 60.4 years). There were statistically significant differences in improvement among ODI items. Surprisingly, the most improvement after surgery was noted in the standing, sex life, and social life domains. The least improvement was noted in the personal care, sleeping, and sitting domains. Linear regression for change in ODI components versus change in SF-12 PCS revealed a significant correlation (R = 0.353, P ≤ 0.001). The only retained domains in the final model were change in lifting, standing, and traveling as predictors for ΔPCS. CONCLUSION: All domains of the ODI do not improve equally after surgery for degenerative spondylolisthesis. Some of the domains that improve most (e.g., sex life) have no discernible relationship to the known pathophysiology of degenerative spondylolisthesis. Based upon these results, we conclude that the item bank and composite scoring of the ODI are inappropriate for evaluating quality of life in studies of surgically treated degenerative spondylolisthesis patients. LEVEL OF EVIDENCE: 3.

Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site.

Fragment-based lead discovery is becoming an increasingly popular strategy for drug discovery. Fragment screening identifies weakly binding compounds that require optimization to become high-affinity leads. As design of leads from fragments is challenging, reliable computational methods to guide optimization would be invaluable. We evaluated using molecular dynamics simulations and the free energy perturbation method (MD/FEP) in fragment optimization for the A2A adenosine receptor, a pharmaceutically relevant G protein-coupled receptor. Optimization of fragments exploring two binding site subpockets was probed by calculating relative binding affinities for 23 adenine derivatives, resulting in strong agreement with experimental data (R2 = 0.78). The predictive power of MD/FEP was significantly better than that of an empirical scoring function. We also demonstrated the potential of the MD/FEP to assess multiple binding modes and to tailor the thermodynamic profile of ligands during optimization. Finally, MD/FEP was applied prospectively to optimize three nonpurine fragments, and predictions for 12 compounds were evaluated experimentally. The direction of the change in binding affinity was correctly predicted in a majority of the cases, and agreement with experiment could be improved with rigorous parameter derivation. The results suggest that MD/FEP will become a powerful tool in structure-driven optimization of fragments to lead candidates.

N6-Substituted 5'-N-Methylcarbamoyl-4'-selenoadenosines as Potent and Selective A3 Adenosine Receptor Agonists with Unusual Sugar Puckering and Nucleobase Orientation.

Potent and selective A3 adenosine receptor (AR) agonists were identified by the replacement of 4'-oxo- or 4'-thionucleosides with bioisosteric selenium. Unlike previous agonists, 4'-seleno analogues preferred a glycosidic syn conformation and South sugar puckering, as shown in the X-ray crystal structure of 5'-N-methylcarbamoyl derivative 3p. Among the compounds tested, N6-3-iodobenzyl analogue 3d was found to be the most potent A3AR full agonist (Ki = 0.57 nM), which was ≥800- and 1900-fold selective for A1AR and A2AAR, respectively. In the N6-cycloalkyl series, 2-Cl analogues generally exhibited better hA3AR affinity than 2-H analogues, whereas 2-H > 2-Cl in the N6-3-halobenzyl series. N7 isomers 3t and 3u were much weaker in binding than corresponding N9 isomers, but compound 3t lacked A3AR activation, appearing to be a weak antagonist. 2-Cl-N6-3-iodobenzyl analogue 3p inhibited chemoattractant-induced migration of microglia/monocytes without inducing cell death at ≤50 µM. This suggests the potential for the development of 4'-selenonucleoside A3AR agonists as novel antistroke agents.

Scaffold Repurposing of Nucleosides (Adenosine Receptor Agonists): Enhanced Activity at the Human Dopamine and Norepinephrine Sodium Symporters.

We have repurposed (N)-methanocarba adenosine derivatives (A3 adenosine receptor (AR) agonists) to enhance radioligand binding allosterically at the human dopamine (DA) transporter (DAT) and inhibit DA uptake. We extended the structure-activity relationship of this series with small N6-alkyl substitution, 5'-esters, deaza modifications of adenine, and ribose restored in place of methanocarba. C2-(5-Halothien-2-yl)-ethynyl 5'-methyl 9 (MRS7292) and 5'-ethyl 10 (MRS7232) esters enhanced binding at DAT (EC50 ∼ 35 nM) and at the norepinephrine transporter (NET). 9 and 10 were selective for DAT compared to A3AR in the mouse but not in humans. At DAT, the binding of two structurally dissimilar radioligands was enhanced; NET binding of only one radioligand was enhanced; SERT radioligand binding was minimally affected. 10 was more potent than cocaine at inhibiting DA uptake (IC50 = 107 nM). Ribose analogues were weaker in DAT interaction than the corresponding bicyclics. Thus, we enhanced the neurotransmitter transporter activity of rigid nucleosides while reducing A3AR affinity.

Structure-Based Scaffold Repurposing for G Protein-Coupled Receptors: Transformation of Adenosine Derivatives into 5HT2B/5HT2C Serotonin Receptor Antagonists.

Adenosine derivatives developed to activate adenosine receptors (ARs) revealed micromolar activity at serotonin 5HT2B and 5HT2C receptors (5HTRs). We explored the structure-activity relationship at 5HT2Rs and modeled receptor interactions in order to optimize affinity and simultaneously reduce AR affinity. Depending on N6 substitution, small 5'-alkylamide modification maintained 5HT2BR affinity, which was enhanced upon ribose substitution with rigid bicyclo[3.1.0]hexane (North (N)-methanocarba), e.g., N6-dicyclopropylmethyl 4'-CH2OH derivative 14 (Ki 11 nM). 5'-Methylamide 23 was 170-fold selective as antagonist for 5HT2BR vs 5HT2CR. 5'-Methyl 25 and ethyl 26 esters potently antagonized 5HT2Rs with moderate selectivity in comparison to ARs; related 6-N,N-dimethylamino analogue 30 was 5HT2R-selective. 5' position flexibility of substitution was indicated in 5HT2BR docking. Both 5'-ester and 5'-amide derivatives displayed in vivo t1/2 of 3-4 h. Thus, we used G protein-coupled receptor modeling to repurpose nucleoside scaffolds in favor of binding at nonpurine receptors as novel 5HT2R antagonists, with potential for cardioprotection, liver protection, or central nervous system activity.