Easing the Entry of Qualified International Medical Graduates to U.S. Medical Practice.

ABSTRACT: Almost one quarter of physicians and physicians-in-training in the United States are international medical graduates (IMGs), meaning they have graduated from a medical school not accredited in the United States. Some IMGs are U.S. citizens and others are foreign nationals. IMGs, many of whom have years of training and experience gained in their countries of origin, have long contributed to the U.S. health care system, especially by providing care to populations that have been historically underserved. Additionally, many IMGs contribute to the diversity of the health care workforce, which can enhance the health of the population. The diversity of the United States is increasing, and racial and ethnic concordance between a physician and a patient has been linked to improved health outcomes.IMGs must meet national- and state-level licensing and credentialing standards like any other U.S. physician. This assures the ongoing quality of the care provided by the medical workforce and protects the public. However, at the state level, variation in standards and standards that may be more challenging to meet than those for U.S. medical school graduates may hamper IMGs' contributions. IMGs who are not U.S. citizens also face visa and immigration barriers.In this article, the authors present insights gleaned from Minnesota's model IMG integration program as well as changes made in 2 states in response to the COVID-19 pandemic. Improving and streamlining processes for IMGs to be licensed and credentialed as well as the policies governing visas and immigration, where appropriate, can ensure that IMGs will be willing and able to continue to practice when and where they are needed. This, in turn, could increase the contribution of IMGs to addressing health care inequities, improving health care access through service in federally designated Health Professional Shortage Areas, and reducing the impact of potential physician shortages.

Supporting Medical Education Innovation: Evaluation of a Grants Initiative.

PROBLEM: Medical education must evolve to meet the changing needs of patients and communities. Innovation is a critical component of that evolution. As medical educators pursue innovative curricula, assessments, and evaluation techniques, the impact of innovations may be limited by minimal funding. The American Medical Association (AMA) Innovation Grant Program, launched in 2018, seeks to address the gap in funding and stimulate educational innovation and research in medical education. APPROACH: In 2018 and 2019, the Innovation Grant Program targeted innovation in content areas including health systems science, competency-based medical education, coaching, learning environment, and emerging technology. The authors reviewed the content of applications and final reports for the 27 projects completed during the first 2 years of the program. They also noted measures of success (completion of project, achievement of grant objectives, development of transferrable educational product, dissemination). OUTCOMES: In 2018, the AMA received 52 submissions and funded 13 proposals, dispersing $290,000 ($10,000 and $30,000 grants). In 2019, the AMA received 80 submissions and funded 15 proposals, dispersing $345,000. Among the 27 completed grants, 17 (63%) supported innovations related to health systems science. Fifteen (56%) were used to create educational products that could be shared, such as new assessment tools, curricula, and teaching modules. Five grant recipients (29%) published articles and 15 (56%) presented at national conferences. NEXT STEPS: The grant program advanced educational innovations, particularly in health systems science. The next steps will involve examining the long-term outcomes and impact of the completed projects on medical students, patients, and the health system; the professional development of the grantees; and the adoption and dissemination of the innovations.

Realizing the vision of the Lancet Commission on Education of Health Professionals for the 21st Century: Transforming medical education through the Accelerating Change in Medical Education Consortium.

In the last two decades, prompted by the anticipated arrival of the 21st Century and on the centenary of the publication of the Flexner Report, many in medical education called for change to address the expanding chasm between the requirements of the health care system and the educational systems producing the health care workforce. Calls were uniform. Curricular content was missing. There was a mismatch in where people trained and where they were needed to practice, legacy approaches to pedagogical methods that needed to be challenged, an imbalance in diversity of trainees, and a lack of research on educational outcomes, resulting in a workforce that was described as ill-equipped to provide health care in the current and future environment. The Lancet Commission on Education of Health Professionals for the 21st Century published a widely acclaimed report in 2010 that called for a complete and authoritative re-examination of health professional education. This paper describes the innovations of the American Medical Association Accelerating Change in Medical Education Consortium schools as they relate to the recommendations of the Lancet Commission. We outline the successes, challenges, and lessons learned in working to deeply reform medical education.

Expanding innovation from undergraduate to graduate medical education: A path of continuous professional development.

A hundred years after the Flexner report laid the foundation for modern medical education, a number of authors commemorated the occasion by commenting on how the medical education system had to change once more to serve 21st century patients. Experts called for standardized outcomes and individualized learner pathways, integration of material across traditional areas, attention to an environment of inquiry, and professional identity formation. The medical education community responded and much has been achieved in the last decade, but much work remains to be done. In this paper we outline how the American Medical Association Accelerating Change in Medical Education Consortium, launched in 2013 through significant funding of transformation projects in undergraduate medical education, expanded its work into graduate medical education, and we look to the future of innovation in medical education.

Improving Our Ability to Predict Resident Applicant Performance: Validity Evidence for a Situational Judgment Test.

Construct: We investigated whether a situational judgment test (SJT) designed to measure professionalism in physicians predicts residents' performance on (a) Accreditation Council for Graduate Medical Education (ACGME) competencies and (b) a multisource professionalism assessment (MPA). Background: There is a consensus regarding the importance of assessing professionalism and interpersonal and communication skills in medical students, residents, and practicing physicians. Nonetheless, these noncognitive competencies are not well measured during medical education selection processes. One promising method for measuring these noncognitive competencies is the SJT. In a typical SJT, respondents are presented with written or video-based scenarios and asked to make choices from a set of alternative courses of action. Interpersonally oriented SJTs are commonly used for selection to medical schools in the United Kingdom and Belgium and for postgraduate selection of trainees to medical practice in Belgium, Singapore, Canada, and Australia. However, despite international evidence suggesting that SJTs are useful predictors of in-training performance, end-of-training performance, supervisory ratings of performance, and clinical skills licensing objective structured clinical examinations, the use of interpersonally oriented SJTs in residency settings in the United States has been infrequently investigated. The purpose of this study was to investigate whether residents' performance on an SJT designed to measure professionalism-related competencies-conscientiousness, integrity, accountability, aspiring to excellence, teamwork, stress tolerance, and patient-centered care-predicts both their current and future performance as residents on two important but conceptually distinct criteria: ACGME competencies and the MPA. Approach: We developed an SJT to measure seven dimensions of professionalism. During calendar year 2017, 21 residency programs from 2 institutions administered the SJT. We conducted analyses to determine the validity of SJT and USMLE scores in predicting milestone performance in ACGME core competency domains and the MPA in June 2017 and 3 months later in September 2017 for the MPA and 1 year later, in June 2018, for ACGME domains. Results: At both periods, the SJT score predicted overall ACGME milestone performance (r = .13 and .17, respectively; p < .05) and MPA performance (r = .19 and .21, respectively; p < .05). In addition, the SJT predicted ACGME patient care, systems-based practice, practice-based learning and improvement, interpersonal and communication skills, and professionalism competencies (r = .16, .15, .15, .17, and .16, respectively; p < .05) 1 year later. The SJT score contributed incremental validity over USMLE scores in predicting overall ACGME milestone performance (ΔR = .07) 1 year later and MPA performance (ΔR = .05) 3 months later. Conclusions: SJTs show promise as a method for assessing noncognitive attributes in residency program applicants. The SJT's incremental validity to the USMLE series in this study underscores the importance of moving beyond these standardized tests to a more holistic review of candidates that includes both cognitive and noncognitive measures.

See No Evil, Hear No Evil, Stop No Evil: Institutional-Level Tracking to Combat Mistreatment of Residents and Fellows.

BACKGROUND: Mistreatment of trainees, including discrimination and harassment, is a problem in graduate medical education. Current tools to assess the prevalence of mistreatment often are not administered institutionally and may not account for multiple sources of mistreatment, limiting an institution's ability to respond and intervene. OBJECTIVE: We describe the utility of a brief questionnaire, embedded within longer institutional program evaluations, measuring the prevalence of different types of trainee mistreatment from multiple sources, including supervisors, team members, colleagues, and patients. METHODS: In 2018, we administered a modified version of the mistreatment questions in the Association of American Medical Colleges Graduation Questionnaire to investigate the prevalence and sources of mistreatment in graduating residents and fellows. We conducted analyses to determine the prevalence, types, and sources of mistreatment of trainees at the institutional level across graduate medical education programs. RESULTS: A total of 234 graduating trainees (77%) from the University of Minnesota-Twin Cities completed the questions. Patients were cited as the primary source of mistreatment in 5 of 6 categories, including both direct and indirect offensive remarks, microaggressions, sexual harassment, and physical threats (paired t test comparisons from t = 3.92 to t = 9.71, all P < .001). The only category of mistreatment in which patients were not the most significant source was humiliation and shaming. CONCLUSIONS: Six questions concerning types and sources of trainee mistreatment, embedded within an institutional survey, generated new information for institutional-, departmental- and program-based future interventions. Patients were the greatest source for all types of mistreatment except humiliation and shaming.

Predicting Performance of First-Year Residents: Correlations Between Structured Interview, Licensure Exam, and Competency Scores in a Multi-Institutional Study.

PURPOSE: To determine whether scores on structured interview (SI) questions designed to measure noncognitive competencies in physicians (1) predict subsequent first-year resident performance on Accreditation Council for Graduate Medical Education (ACGME) milestones and (2) add incremental validity over United States Medical Licensing Examination (USMLE) Step 1 and Step 2 Clinical Knowledge scores in predicting performance. METHOD: The authors developed 18 behavioral description questions to measure key noncognitive competencies (e.g., teamwork). In 2013-2015, 14 programs (13 residency, 1 fellowship) from 6 institutions used subsets of these questions in their selection processes. The authors conducted analyses to determine the validity of SI and USMLE scores in predicting first-year resident milestone performance in the ACGME's core competency domains and overall. RESULTS: SI scores predicted midyear and year-end overall performance (r = 0.18 and 0.19, respectively, P < .05) and year-end performance on patient care, interpersonal and communication skills, and professionalism competencies (r = 0.23, r = 0.22, and r = 0.20, respectively, P < .05). SI scores contributed incremental validity over USMLE scores in predicting year-end performance on patient care (ΔR = 0.05), interpersonal and communication skills (ΔR = 0.09), and professionalism (ΔR = 0.09; all P < .05). USMLE scores contributed incremental validity over SI scores in predicting year-end performance overall and on patient care and medical knowledge. CONCLUSIONS: SI scores predict first-year resident year-end performance in the interpersonal and communication skills, patient care, and professionalism competency domains. Future research should investigate whether SIs predict a range of clinically relevant outcomes.

Delayed Treatment Acceleration in Patients with Rheumatoid Arthritis Who Have Inadequate Response to Initial Tumor Necrosis Factor Inhibitors: Data from the Corrona Registry.

BACKGROUND: The implementation of treat-to-target principles in rheumatoid arthritis (RA) has not been fully investigated in patients with inadequate response to tumor necrosis factor (TNF) inhibitor treatment. OBJECTIVES: To evaluate the prevalence of an inadequate response to initial TNF inhibitor treatment at 6 and 12 months among patients with RA in a real-world patient registry, as well as the delay in therapy adjustment and its impact on disease activity and patient-reported outcome (PRO) measures. METHODS: This analysis is based on data of patients with moderate or severe disease activity (Clinical Disease Activity Index [CDAI] score >10) who were included in the Consortium of Rheumatology Researchers of North America (Corrona) RA registry, a prospective, observational database. The patients had never received treatment with a biologic disease-modifying antirheumatic drug (DMARD) and had initiated treatment with a TNF inhibitor (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab) between October 2001 and December 2014. We evaluated treatment response (CDAI score ≤10), select PRO measures, and treatment changes at 6 months. Patients who had an inadequate response to TNF inhibitor therapy at 6 months and continued to use their initial TNF inhibitor were evaluated again at 12 months. RESULTS: This retrospective analysis included 2282 patients. At 6 months, 1732 (75.9%) of the patients continued to use their initial TNF inhibitor; of these, 803 (46.4%) patients had an inadequate response to treatment. Of the 803 patients who had an inadequate response at 6 months, 488 (60.8%) continued their initial treatment at 12 months. Of these 488 patients, 315 (64.5%) had an inadequate response at 12 months, and 173 (35.5%) had a response. Numerically greater improvements in all PRO measures were observed for patients who responded to therapy compared with patients with an inadequate response. CONCLUSIONS: In this real-world analysis of data from the Corrona RA registry, a considerable proportion of patients with RA had an inadequate response to the initial TNF inhibitor therapy at 6 and 12 months. Many patients continued to have moderate or high disease activity, without accelerating treatment (eg, addition or increase in the dose of concurrent conventional synthetic DMARDs or a TNF inhibitor), contrary to treat-to-target principles, thus remaining at risk for accumulating joint damage and disability.

Education in Pediatrics Across the Continuum (EPAC): First Steps Toward Realizing the Dream of Competency-Based Education.

The Education in Pediatrics Across the Continuum (EPAC) Study Group is developing the first competency-based, time-variable progression from undergraduate medical education (UME) to graduate medical education (GME) in the history of medical education in the United States. EPAC, an innovation project sponsored by the Association of American Medical Colleges and supported by the Josiah Macy Jr. Foundation, was developed through a collaboration between five medical schools and multiple professional organizations with an interest in undergraduate and graduate medical education. The planning and implementation process demanded cooperatively addressing practical barriers such as education requirements for licensure and developing approaches to learner assessment that provided meaningful information about competency. Each participating school now has at least three cohorts of learners participating, and the program is transitioning its first cohort of students from UME to GME based on achievement of predetermined competencies that allow this transition. Members of the first cohort of learners in this program have begun their pediatric residency training at different times beginning in late 2016, confirming the feasibility of competency-based advancement from UME to GME in pediatrics. Although there is still much to learn about the outcomes of EPAC learners' professional development in residency training and beyond, EPAC has defined an operational approach to a different path through medical school and into residency training, based on the attainment of competence.

Not all unprofessional behaviors are equal: The creation of a checklist of bad behaviors.

INTRODUCTION: Professionalism is a key component of medical education and training. However, there are few tools to aid educators in diagnosing unprofessional behavior at an early stage. The purpose of this study was to employ policy capturing methodology to develop two empirically validated checklists for identifying professionalism issues in early-career physicians. METHOD: In a series of workshops, a professionalism competency model containing 74 positive and 70 negative professionalism behaviors was developed and validated. Subsequently, 23 subject matter experts indicated their level of concern if each negative behavior occurred 1, 2, 3, 4, or 5 or more times during a six-month period. These ratings were used to create a "brief" and "extended" professionalism checklist for monitoring physician misconduct. RESULTS: This study confirmed the subjective impression that some unprofessional behaviors are more egregious than others. Fourteen negative behaviors (e.g. displaying obvious signs of substance abuse) were judged to be concerning if they occurred only once, whereas many others (e.g. arriving late for conferences) were judged to be concerning only when they occurred repeatedly. DISCUSSION: Medical educators can use the professionalism checklists developed in this study to aid in the early identification and subsequent remediation of unprofessional behavior in medical students and residents.

Accuracy of self-monitoring during learning of radiograph interpretation.

CONTEXT: Despite calls for the improvement of self-assessment as a basis for self-directed learning, instructional designs that include reflection in practice are uncommon. Using data from a screen-based simulation for learning radiograph interpretation, we present validity evidence for a simple self-monitoring measure and examine how it can complement skill assessment. METHODS: Medical students learning ankle radiograph interpretation were given an online learning set of 50 cases which they were asked to classify as 'abnormal' (fractured) or 'normal' and to indicate the degree to which they felt certain about their response (Definitely or Probably). They received immediate feedback on each case. All students subsequently completed two 20-case post-tests: an immediate post-test (IPT), and a delayed post-test (DPT) administered 2 weeks later. We determined the degree to which certainty (Definitely versus Probably) correlated with accuracy of interpretation and how this relationship changed between the tests. RESULTS: Of 988 students approached, 115 completed both tests. Mean ± SD accuracy scores decreased from 59 ± 17% at the IPT to 53 ± 16% at the DPT (95% confidence interval [CI] for the difference: -2% to -10%). Mean self-assessed certainty did not decrease (rates of Definitely: IPT, 17.6%; DPT, 19.5%; 95% CI for difference: +7.2% to -3.4%). Regression modelling showed that accuracy was positively associated with choosing Definitely over Probably (odds ratio [OR] 1.63, 95% CI 1.27-2.09) and indicated a statistically significant interaction between test timing and certainty (OR 0.72, 95% CI 0.52-0.99); thus, the accuracy of self-monitoring decayed over the retention interval, leaving students relatively overconfident in their abilities. CONCLUSIONS: This study shows that, in medical students learning radiograph interpretation, the development of self-monitoring skills can be measured and should not be assumed to necessarily vary in the same way as the underlying clinical skill.

NXN-188, a selective nNOS inhibitor and a 5-HT1B/1D receptor agonist, inhibits CGRP release in preclinical migraine models.

BACKGROUND: NXN-188 is a combined neuronal nitric oxide synthase (nNOS) inhibitor and 5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptor agonist. Using preclinical models, we evaluated whether these two unique therapeutic principles have a synergistic effect in attenuating stimulated calcitonin gene-related peptide (CGRP) release, a marker of trigeminal activation. METHODS: We examined the effect of NXN-188 on: (1) KCl-, capsaicin- and resiniferatoxin (RTX)-induced immunoreactive CGRP (iCGRP) release from isolated preparation of rat dura mater, trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC); and (2) capsaicin- and electrical stimulation (ES)-induced middle meningeal artery (MMA) dilation in a rat closed-cranial window. RESULTS: NXN-188 inhibited: (1) KCl-stimulated iCGRP release from dura mater (% decrease mean ± SEM, lowest effective concentration) (35 ± 6%, 30 µM), TG (24 ± 11%, 10 µM) and TNC (40 ± 8%, 10 µM); (2) capsaicin- and RTX-induced iCGRP release from dura mater; and (3) capsaicin- and ES-induced increase in dural artery diameter (32 ± 5%, 3 mg kg(-1) intravenous (i.v.) and 36 ± 1%, 10 mg kg(-1) i.v.). CONCLUSIONS: NXN-188 inhibits CGRP release from migraine-relevant cephalic tissues. Its effect is most likely mediated via a combination of nNOS-inhibition and 5-HT1B/1D receptor agonism in dura mater while the mechanisms of action for inhibition of CGRP release from TG and TNC have to be investigated further.

Discovery of a potent, orally bioavailable and highly selective human neuronal nitric oxide synthase (nNOS) inhibitor, N-(1-(piperidin-4-yl)indolin-5-yl)thiophene-2-carboximidamide as a pre-clinical development candidate for the treatment of migraine.

We recently reported a series of 1,6-disubstituted indoline-based thiophene amidine compounds (5) as selective neuronal nitric oxide synthase (nNOS) inhibitors to mitigate the cardiovascular liabilities associated with hERG K(+) channel inhibition (IC(50) = 4.7 µM) with previously reported tetrahydroquinoline-based selective nNOS inhibitors (4). The extended structure-activity relationship studies within the indoline core led to the identification of 43 as a selection candidate for further evaluations. The in vivo activity in two different pain (spinal nerve ligation and migraine pain) models, the excellent physicochemical and pharmacokinetic properties, oral bioavailability (F(po) = 91%), and the in vitro safety profile disclosed in this report make 43 an ideal candidate for further evaluation in clinical applications related to migraine pain.

First-in-class, dual-action, 3,5-disubstituted indole derivatives having human nitric oxide synthase (nNOS) and norepinephrine reuptake inhibitory (NERI) activity for the treatment of neuropathic pain.

A family of different 3,5-disubstituted indole derivatives having 6-membered rings were designed, synthesized, and demonstrated inhibition of human nitric oxide synthase (NOS) with norepinephrine reuptake inhibitory activity (NERI). The structure-activity relationship (SAR) within the cyclohexane ring showed the cis-isomers to be more potent for neuronal NOS and selective over endothelial NOS compared to their trans-counterparts. Compounds, such as cis-(+)-37, exhibited dual nNOS and NET inhibition (IC(50) of 0.56 and 1.0 µM, respectively) and excellent selectivity (88-fold and 12-fold) over eNOS and iNOS, respectively. The lead compound (cis-(+)-37) showed lack of any direct vasoconstriction or inhibition of ACh-mediated vasorelaxation in isolated human coronary arteries. Additionally, cis-(+)-37 was effective at reversing both allodynia and thermal hyperalgesia in a standard Chung (spinal nerve ligation) rat neuropathic pain model. Overall, the data suggest that cis-(+)-37 is a promising dual action development candidate having therapeutic potential for the treatment of neuropathic pain.

Novel, druglike 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine-based selective inhibitors of human neuronal nitric oxide synthase (nNOS).

A novel class of 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine derivatives was designed, synthesized and evaluated as human nitric oxide synthase (NOS) inhibitors. Structure-activity relationship studies based on various basic amine side chains attached at the 1-position of the 2,3,4,5-tetrahydro-1H-benzo[b]azepine ring led to the identification of several potent and highly selective inhibitors (17, 18, 25, (±)-39, and (±)-40) of human neuronal NOS. The potential therapeutic application of one of these new selective nNOS inhibitors (17) was demonstrated in an in vivo spinal nerve ligation model of neuropathic pain, and various in vitro safety pharmacology studies such as the hERG K(+) channel inhibition assay and high throughput broad screen (minimal activity at 79 receptors/transporters/ion channels).

3,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase (nNOS) inhibitors.

A series of 3,5-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). Various guanidine isosteric groups were explored at the 5-position of the indole ring, while keeping the basic amine side chain such as N-methylpiperidine ring, fixed at the 3-position of the indole ring. Compounds having 2-thiophene amidine and 2-furanyl amidine groups (7, 8, 10 and 12) showed increased activity for human neuronal NOS and good selectivity over endothelial and inducible NOS isoforms. Compound 8 was shown to reverse (10mg/kg, ip) thermal hyperalgesia in the L(5)/L(6) spinal nerve ligation (neuropathic pain) model and was devoid of any significant drug-drug interaction potential due to cytochrome P450 inhibition or cardiovascular liabilities associated with the inhibition of endothelial NOS.

Prevalence of abnormal cases in an image bank affects the learning of radiograph interpretation.

OBJECTIVES: Using a large image bank, we systematically examined how the use of different ratios of abnormal to normal cases affects trainee learning. METHODS: This was a prospective, double-blind, randomised, three-arm education trial conducted in six academic training programmes for emergency medicine and paediatric residents in post-licensure years 2-5. We developed a paediatric ankle trauma radiograph case bank. From this bank, we constructed three different 50-case training sets, which varied in their proportions of abnormal cases (30%, 50%, 70%). Levels of difficulty and diagnoses were similar across sets. We randomly assigned residents to complete one of the training sets. Users classified each case as normal or abnormal, specifying the locations of any abnormalities. They received immediate feedback. All participants completed the same 20-case post-test in which 40% of cases were abnormal. We determined participant sensitivity, specificity, likelihood ratio and signal detection parameters. RESULTS: A total of 100 residents completed the study. The groups did not differ in accuracy on the post-test (p = 0.20). However, they showed considerable variation in their sensitivity-specificity trade-off. The group that received a training set with a high proportion of abnormal cases achieved the best sensitivity (0.69, standard deviation [SD] = 0.24), whereas the groups that received training sets with medium and low proportions of abnormal cases demonstrated sensitivities of 0.63 (SD = 0.21) and 0.51 (SD = 0.24), respectively (p < 0.01). Conversely, the group with a low proportion of abnormal cases demonstrated the best specificity (0.83, SD = 0.10) compared with the groups with medium (0.70, SD = 0.15) and high (0.66, SD = 0.17) proportions of abnormal cases (p < 0.001). The group with a low proportion of abnormal cases had the highest false negative rate and missed fractures one-third more often than the groups that trained on higher proportions of abnormal cases. CONCLUSIONS: Manipulating the ratio of abnormal to normal cases in learning banks can have important educational implications.

Discovery of cis-N-(1-(4-(methylamino)cyclohexyl)indolin-6-yl)thiophene-2-carboximidamide: a 1,6-disubstituted indoline derivative as a highly selective inhibitor of human neuronal nitric oxide synthase (nNOS) without any cardiovascular liabilities.

A series of 1,6-disubstituted indoline derivatives were synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS) designed to mitigate the cardiovascular liabilities associated with previously reported tetrahydroquinoline-based selective neuronal NOS inhibitors due to higher lipophilicity ( J. Med. Chem. 2011 , 54 , 5562 - 5575 ). This new series produced similar potency and selectivity among the NOS isoforms and was devoid of any cardiovascular liabilities associated with QT prolongation due to hERG activity or endothelial NOS mediated vasoconstriction effect. The SAR studies led to the identification of cis-45, which was shown to reverse thermal hyperalgesia in vivo in the spinal nerve ligation model of neuropathic pain with excellent safety profile (off-target activities at 80 CNS related receptors/ion channels/transporters). The results presented in this report make cis-45 as an ideal tool for evaluating the potential role of selective nNOS inhibitors in CNS related disorders where excess NO produced by nNOS is thought to play a crucial role.

NOpiates: Novel Dual Action Neuronal Nitric Oxide Synthase Inhibitors with µ-Opioid Agonist Activity.

A novel series of benzimidazole designed multiple ligands (DMLs) with activity at the neuronal nitric oxide synthase (nNOS) enzyme and the µ-opioid receptor was developed. Targeting of the structurally dissimilar heme-containing enzyme and the µ-opioid GPCR was predicated on the modulatory role of nitric oxide on µ-opioid receptor function. Structure-activity relationship studies yielded lead compound 24 with excellent nNOS inhibitory activity (IC50 = 0.44 µM), selectivity over both endothelial nitric oxide synthase (10-fold) and inducible nitric oxide synthase (125-fold), and potent µ-opioid binding affinity, K i = 5.4 nM. The functional activity as measured in the cyclic adenosine monosphospate secondary messenger assay resulted in full agonist activity (EC50 = 0.34 µM). This work represents a novel approach in the development of new analgesics for the treatment of pain.