General self-efficacy, not musculoskeletal health, was associated with social isolation and loneliness in older adults during the COVID-19 pandemic: findings from the Hertfordshire Cohort Study.

BACKGROUND: Social isolation and loneliness are prevalent among older adults. This study investigated factors influencing worsening social isolation and loneliness in community-dwelling older adults during the COVID-19 pandemic, focusing on musculoskeletal conditions, falls, and fractures. METHODS: We studied 153 participants from the Hertfordshire Cohort Study. Baseline assessments (2019-20) included osteoporosis, clinical osteoarthritis, fractures after age 45 years, falls in previous year, and lifestyle factors. Self-efficacy was assessed using a shortened General Self-Efficacy Scale. Social isolation was assessed using the 6-item Lubben Social Network Scale. Follow-up (2020-21) assessments included social isolation and loneliness using the 6-item De Jong-Gierveld scale for emotional, social, and overall loneliness. RESULTS: Baseline median age was 83.1 years. A history of smoking predicted worsening social isolation (p = 0.046). Being married (p = 0.026) and higher self-efficacy scores (p = 0.03) predicted reduced social isolation at follow-up. Greater alcohol consumption was associated with higher overall loneliness (p = 0.026). Being married was related to a 36% (95% CI: 3%, 58%) reduction in emotional loneliness (p = 0.037). No musculoskeletal condition was associated with social isolation or loneliness. However, we observed a 22% (14%, 30%; p < 0.001) reduction in emotional loneliness and a 12% (4%, 20%; p = 0.003) reduction in overall loneliness per unit increase in self-efficacy score. CONCLUSIONS: No musculoskeletal condition was associated with increased social isolation or loneliness, but longitudinal studies in larger samples are required. Greater self-efficacy was associated with reduced social isolation and reduced loneliness. Interventions promoting self-efficacy in older adults may reduce isolation and loneliness in this age group.

Investigating the relationship between self-perception of fracture risk and prior fracture: findings from the Hertfordshire Cohort Study.

BACKGROUND: Self-perceived risk of fracture (SPR) is associated with fracture independent of FRAX calculated risk. To understand this better we considered whether lifestyle factors not included in the FRAX algorithm and psychosocial factors (social isolation, self-efficacy, or mental health status) explain the relationship between SPR and fracture. METHODS: We studied 146 UK community-dwelling older adults from the Hertfordshire Cohort Study. SPR ranked as 'lower', 'similar' and 'higher' relative to others of the same age, was assessed by questionnaire. Social isolation was assessed using the six-item Lubben Social Network Scale; self-efficacy was assessed using a shortened General Self-Efficacy Scale (GSE); mental health status was assessed using the anxiety/depression item from the EuroQoL questionnaire. SPR in relation to previous self-reported fracture was examined using logistic regression. RESULTS: Among participants of median age 83.4 (IQR 81.5-85.5) years, SPR was lower for 54.1% of participants, similar for 30.8%, and higher for 15.1%; 74.7% reported no previous fractures. Greater SPR was associated with increased odds of previous fractures when adjusting for sex and age only (OR 1.72, 95% CI 1.03-2.87, per higher band of SPR). While further individual adjustment for social isolation (1.73, 1.04-2.89), self-efficacy (1.71, 1.02-2.85), or mental health (1.77, 1.06-2.97) did not attenuate the relationship, individual adjustment for diet quality and number of comorbidities did. CONCLUSIONS: Adjustment for social isolation, self-efficacy or mental health status did not attenuate the relationship between SPR and fracture. By contrast, lifestyle factors not included in FRAX, such as diet quality, did attenuate relationships, suggesting a possible future area of investigation.

Is Regular Weight-Bearing Physical Activity Throughout the Lifecourse Associated with Better Bone Health in Late Adulthood?

We considered how weight-bearing physical activity (WBPA) through the lifecourse related to bone health in late adulthood in the Hertfordshire Cohort Study (HCS), a cohort of community dwelling adults born 1931-9, to identify sex-specific differences and periods critical for optimal bone health. Available questionnaire data from 258 participants (128 men and 130 women) included current reported lifestyle factors (including physical activity) and WBPA, coded as participation in WBPA aged < 18 years; aged 18-29 years; aged 30-49 years and aged ≥ 50 years. Responses were recorded as none/once a month/once a week/> once a week. Hip bone mineral density (BMD) was measured using a Lunar Prodigy DXA scanner. The mean age was 75.4 (SD 2.5) years in men and 75.7 (SD 2.6) years in women. Men reported significantly higher levels of past WBPA aged < 18 years (p = 0.006) and aged 18-29 years than women (p < 0.001). We observed greater BMD at total hip in women who reported regular WBPA at ages 18-29 years (p = 0.02) and 30-49 years (p = 0.02) compared with those who reported no WBPA (p = 0.019), after adjustment for confounders including current activity levels. In this cohort of older adults, recalled regular WBPA around the time of peak bone mass acquisition was less common in women than men, but associated with higher hip BMD in women in late adulthood.

Nutritional risk and its relationship with physical function in community-dwelling older adults.

BACKGROUND: Malnutrition is a serious concern in older populations. Simple screening approaches are needed to identify signs of early nutritional risk in older people, to allow intervention before overt malnutrition develops, along with the poorer health outcomes associated with it, such as sarcopaenia and frailty. The main aim of this study was to compare nutrition risk scores, calculated from the DETERMINE Checklist ('Determine Your Nutritional Health', also known as the Nutrition Screening Initiative Checklist), with physical function variables in a group of community-dwelling older adults. Another aim was to assess the prevalence of nutrition risk using the DETERMINE and the MUST (Malnutrition Universal Screening Tool). METHODS: Participants of the Hertfordshire Cohort Study (HCS) were recruited and visited at home by a trained researcher. Self-reported physical function was assessed using the SF-36 PF (Short Form-36 Physical Function) scale. The Short Physical Performance Battery (SPPB) was performed, which included the assessment of gait speed, chair rise time and standing balance. Handgrip strength was measured using a Jamar dynamometer. Frailty was assessed according to the presence of at least three of the following Fried frailty criteria: unintentional weight loss, weakness, self-reported exhaustion, slow gait speed and low physical activity. Nutrition risk scores were calculated from the DETERMINE checklist (range 0-21). Nutritional risk was also assessed using the MUST. Analyses were adjusted for sex, age, age left education and number of comorbidities. RESULTS: In the study, 176 participants (94 men and 82 women), median age 83.3 (IQR 81.5-85.7) years, were assessed. Almost half (47%) scored either 'moderate' (score 3-5) or 'high' (score ≥ 6) nutritional risk (9% were at high risk), using the DETERMINE checklist, whereas 8% were at risk using the MUST. Higher nutrition risk scores, calculated from DETERMINE, were associated with poorer self-reported physical function (difference in SF-36 PF score: - 0.36, 95% CI (- 0.60, - 0.12) SD per unit increase in nutrition risk score, P = 0.004) and higher odds of being frail (odds ratio Fried frailty: 2.23, 95% CI (1.15, 4.33), P = 0.017). There were no significant associations between DETERMINE nutrition risk scores and the other variables examined. CONCLUSION: Cross-sectional associations between higher nutrition risk scores, assessed from the DETERMINE checklist, and poorer self-reported physical function and greater likelihood of frailty suggest that this screening tool may have utility for screening older populations. Prospective studies are required to explore the ability of the tool to predict poor physical function and frailty, though these data suggest it has potential for early, simple detection of nutritional problems in community-living older adults.

Relationships between non-communicable disease, social isolation and frailty in community dwelling adults in later life: findings from the Hertfordshire Cohort Study.

BACKGROUND: Social relationships play a fundamental role in individuals' lives and health, and social isolation is prevalent among older people. Chronic non-communicable diseases (NCDs) and frailty are also common in older adults. AIMS: To examine the association between number of NCDs and social isolation in a cohort of community-dwelling older adults in the UK, and to consider whether any potential association is mediated by frailty. METHODS: NCDs were self-reported by 176 older community-dwelling UK adults via questionnaire. Social isolation was assessed using the six-item Lubben Social Network Scale. Frailty was assessed by the Fried phenotype of physical frailty. RESULTS: The median (IQR) age of participants in this study was 83.1 (81.5-85.5) years for men and 83.8 (81.5-85.9) years for women. The proportion of socially isolated individuals was 19% in men and 20% in women. More women (18%) than men (13%) were identified as frail. The number of NCDs was associated with higher odds of being isolated in women (unadjusted odds ratio per additional NCD: 1.65, 95% CI 1.08, 2.52, p = 0.021), but not in men, and the association remained robust to adjustment, even when accounting for frailty (OR 1.85, 95% CI 1.06, 3.22, p = 0.031). DISCUSSION: Number of self-reported NCDs was associated with higher odds of social isolation in women but not in men, and the association remained after considering frailty status. CONCLUSIONS: Our observations may be considered by healthcare professionals caring for community-dwelling older adults with multiple NCDs, where enquiring about social isolation as part of a comprehensive assessment may be important.

The association between social isolation and musculoskeletal health in older community-dwelling adults: findings from the Hertfordshire Cohort Study.

PURPOSE: Social isolation has been associated with both physical and psychological adverse outcomes and is prevalent in older adults. We investigated the impact of social isolation on bone mineral density (BMD) and physical capability in community-dwelling older adults. METHODS: Data were collected in 2011 and 2017 from the Hertfordshire Cohort Study. In 2011, we assessed social isolation using the six-item Lubben Social Network Scale (LSNS-6) and the Maastricht Social Participation Profile (MSSP) and depressive and anxiety symptoms using the Hospital Anxiety and Depression Scale (HADS). Physical capability was assessed by performing tests of gait speed, chair stands, timed up and go and balance at both time points. BMD was assessed using dual X-ray absorptiometry (DXA) at both time points. RESULTS: Data were available from 369 participants in 2011 and 184 in 2017. Forty percent of men and 42.4% of women were socially isolated. Isolated participants had higher odds of depressive disorder (OR 3.01, 95% CI 1.27-7.11, p < 0.02). Social isolation at baseline was associated with poor physical capability scores at follow-up (OR 5.53, 95% CI 1.09-27.99, p < 0.04). No associations were found between social isolation and BMD at either time point. CONCLUSIONS: Social isolation was associated with higher odds of having depressive symptoms and predicted the development of poor physical capability 6 years later. Further longitudinal studies that include loneliness as a covariate are warranted.

Osteoporosis epidemiology using international cohorts.

PURPOSE OF REVIEW: The field of osteoporosis research has been active for the past 20 years and has allowed significant advancement in the management of osteoporosis. This review will give an overview of the latest data from international cohorts that relate to current and recent osteoporosis research. RECENT FINDINGS: The clinical diagnosis of osteoporosis relies heavily on bone mineral density (BMD) measured at femoral neck or spine and although BMD has excellent predictive value for future fractures, fracture risk assessment has evolved over the years, resulting in the birth of fracture prediction tools. Fracture risk factors not currently featured in these tools are being considered for inclusion, including imminent risk fracture following a sentinel fracture, number of falls, and previous vertebral fractures. Data from groups with comorbidities such as chronic obstructive pulmonary disease are helping us understand how to best manage patients with multiple comorbidities. Finally, the prevalence of vertebral fracture in the older general population and other selected populations has been explored, alongside the global burden of osteoporosis and its consequences. SUMMARY: Our understanding of osteoporosis continues to expand, but knowledge gaps remain.

Medical history, medication use and physical activity in adults in their eighth and ninth decade of life in the Hertfordshire Cohort Study.

While there are many known health benefits to maintained physical activity levels in late adulthood, there have been very few studies that have considered relationships between morbidity profile and physical activity in the eighth decade of life. We studied 1097 participants, 555 men and 542 women from the Hertfordshire Cohort Study, a UK community based sample. Validated questionnaire based data were used to relate self-reported physical activity (PA) levels to medical history, and medication use. Regression analyses were adjusted for age, BMI, smoker status, alcohol consumption. The mean (SD) age of participants in the study was 80.2 (2.7) years for men and 80.2 (2.6) for women. A higher proportion of men (33.7 %) than women (24 %) were in the high activity score group. 20.8 % of female participants and 22.6 % male participants reported having no comorbid disease; 10.5 % men and 8.4 % women were taking no medication. Higher number of chronic conditions was associated with lower levels of PA [men (OR 0.73, 95 % CI 0.63-0.84, p<0.001); women (OR 0.74, 95 % CI 0.64-0.86, p<0.001)] as was being prescribed a higher number of medications [men (OR 0.88, 95 % CI 0.84-0.93, p<0.001); women (OR 0.86, 95 % CI 0.82-0.91, p<0.001)]. All these associations remained robust following adjustments. Strong relationships were seen in both sexes between PA and taking medication for disorders of the central nervous system and gastrointestinal system, with relationships generally stronger in men. We have observed relationships between comorbid medical history and medication use with physical activity in a cohort of community dwelling older adults. These highlight the need to consider medical history when considering how best to optimize PA in older adults.

Understanding influences on physical activity participation by older adults: A qualitative study of community-dwelling older adults from the Hertfordshire Cohort Study, UK.

BACKGROUND: The health benefits of physical activity (PA) participation in later life are widely recognised. Understanding factors that can influence the participation of community-dwelling older adults in PA is crucial in an ageing society. This will be paramount in aiding the design of future interventions to effectively promote PA in this population. The main aim of this qualitative study was to explore influences on PA among community-dwelling older people, and the secondary aim was to explore gender differences. METHODS: Qualitative data were collected in 2014 by conducting focus group discussions using a semi-structured discussion guide with older people resident in Hertfordshire, UK. Discussions were audio-recorded, transcribed verbatim and transcripts analysed thematically. RESULTS: Ninety-two participants were recruited to the study (47% women; 74-83 years) and a total of 11 focus groups were conducted. Findings indicated six themes that appeared to affect older adults' participation in PA: past life experiences; significant life events; getting older; PA environment; psychological/personal factors; and social capital. Overall, the findings emphasised the role of modifiable factors, namely psychological factors (such as self-efficacy, motivation, outcome expectancy) and social factors (such as social support and social engagement). These factors exerted their own influence on physical activity participation, but also appeared to mediate the effect of other largely non-modifiable background and ageing-related factors on participants' engagement with PA in later life. CONCLUSION: In view of these findings, intervention designers could usefully work with behavioural scientists for insight as to how to enhance psychological and social factors in older adults. Our data suggest that interventions that aim to build self-efficacy, motivation and social networks have the potential to indirectly promote PA participation in older adults. This would be best achieved by developing physical activity interventions through working with participants in an empowering and engaging way.

Impact of the COVID-19 pandemic on community-dwelling older adults: A longitudinal qualitative study of participants from the Hertfordshire Cohort Study.

BACKGROUND: Older adults have been especially vulnerable to adverse effects from the COVID-19 pandemic including higher mortality and more severe disease complications. At the same time, social isolation, malnutrition and physical inactivity are serious concerns among older adults. The pandemic and associated restrictions may serve to exacerbate these issues, presenting increased risks to physical and mental health. The aims of this qualitative study were: i) to explore how community-living older people in the UK experienced the first wave of the COVID-19 pandemic, specifically how it impacted their well-being and associated health behaviours; ii) to explore how older people's experiences and behaviours changed over time throughout the first wave. METHODS: Qualitative data were collected by conducting serial telephone interviews, with an interval of approximately three months. Participants were from the Hertfordshire Cohort Study, all aged over 80 years. Discussions were audio-recorded, information related to the COVID-19 pandemic was transcribed verbatim and transcripts analysed thematically. Interviews were conducted from March to October 2020. RESULTS: Data for twelve participants (7 men and 5 women) from a total of 35 interviews were used, comprising two or three timepoints per participant. Analysis identified five overarching themes: 1) shopping strategies and food accessibility, 2) limitations on activities and going out, 3) disruption to healthcare, 4) social and psychological repercussions, and 5) coping strategies. Findings highlight challenges associated with accessing shops, healthcare, and usual activities due to pandemic-related restrictions. Longitudinal findings showed that for some, the ongoing pandemic and related restrictions appeared to aggravate mental health issues (low mood, anxiety) over time, as well as greater feelings of isolation or loneliness, reduced activity and functional limitations; this was despite some relaxation of restrictions later on. Coping strategies used by participants included finding ways to keep busy and to do physical activity safely, maintaining social contact remotely, and having an optimistic or positive outlook, a 'do what you can' attitude. CONCLUSIONS: Interventions are likely to be needed in the wake of the COVID-19 pandemic to support health behaviours, such as increasing physical activity, social engagement and improving mental health among community-living older adults.

Physical Activity and Diet in a Global Pandemic: An Investigation of the Impact of COVID-19 on Factors Relevant for Musculoskeletal Health at Two Different Stages of the Lifecourse.

Background: Physical activity, nutrition and other lifestyle factors play important roles in maintaining musculoskeletal health. The coronavirus disease (COVID-19) originated in late 2019, spread globally to be declared a pandemic by the World Health Organisation in March 2020, and led to widespread behaviour change. The aim of this study was to use two existing cohorts, the Hertfordshire Cohort Study (HCS) and Health and Employment After Fifty Study (HEAF), to understand how wave one of the COVID-19 pandemic impacted lifestyle factors associated with musculoskeletal health in the UK. Methods: 125 eligible participants, 65 males and 60 females (drawn from the HCS study, median (IQR) age 84.3 (82.4-86.6) years, all Caucasian, and community dwelling) were contacted by telephone and asked to complete a questionnaire administered by a trained researcher. Data collection occurred over the period July 2020 to February 2021. 2469 participants, 1086 men and 1383 women (drawn from the HEAF study, median age 65.7 (62.0-69.3) years, mostly Caucasian and community dwelling) completed an online questionnaire in March 2021. Results: In HCS, 47% respondents reported being less physically active than before the pandemic (and only 5% more so), 27% said they consumed less alcohol compared to pre-pandemic times (and only 3% more so), and 18% reported eating less than before, although quality of diet was generally unchanged over this timeframe surveyed. In HEAF, 44% participants said they were less active than before the pandemic, while 17% reported being more active. The majority of participants reported no changes in alcohol consumption and diet; however, 19% said they drank more than before (32% of which was above recommended levels), 16% said their diet was less healthy, and 19% reported eating more than before. Conclusion: We have reported the experience of the first wave of the COVID-19 pandemic among participants of two Caucasian community dwelling UK cohorts, highlighting the impact of the pandemic on lifestyle factors associated with musculoskeletal health. Changed physical activity levels were reported in a high proportion of respondents in both studies; an investigation of reversibility of these changes is required.

Characterization of vabicaserin (SCA-136), a selective 5-hydroxytryptamine 2C receptor agonist.

The 5-hydroxytryptamine 2C (5-HT(2C)) receptor subtype has received considerable attention as a target for drug discovery, having been implicated in a wide variety of disorders. Here, we describe the in vitro pharmacological profile of the novel 5-HT(2C) receptor-selective agonist vabicaserin [(-)-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c] [1,4]diazepino[6,7,1-ij]quinoline hydrochloride] (SCA-136), including a comprehensive strategy to assess 5-HT(2B) receptor selectivity using diverse preparations and assays of receptor activation. Vabicaserin displaced (125)I-(2,5-dimethoxy)phenylisopropylamine binding from human 5-HT(2C) receptor sites in Chinese hamster ovary cell membranes with a K(i) value of 3 nM and was >50-fold selective over a number of serotonergic, noradrenergic, and dopaminergic receptors. Binding affinity determined for the human 5-HT(2B) receptor subtype using [(3)H]5HT was 14 nM. Vabicaserin was a potent and full agonist (EC(50), 8 nM; E(max), 100%) in stimulating 5-HT(2C) receptor-coupled calcium mobilization and exhibited 5-HT(2A) receptor antagonism and 5-HT(2B) antagonist or partial agonist activity in transfected cells, depending on the level of receptor expression. In rat stomach fundus and human colonic longitudinal muscle endogenously expressing 5-HT(2B) receptors, vabicaserin failed to induce a 5-HT(2B) receptor-dependent contraction and produced a rightward shift of the 5-HT and α-methyl-5-HT concentration-response curves in these preparations, respectively, consistent with 5-HT(2B) competitive antagonism. Likewise, vabicaserin failed to induce a 5-HT(2B) receptor-mediated contraction in arteries from deoxycorticosterone acetate-salt-treated rats, a model of hypersensitized 5-HT(2B) receptor function, and produced a rightward shift in the 5-HT-induced response that was consistent with 5-HT(2B) receptor antagonism. In summary, vabicaserin is a novel, potent, and selective 5-HT(2C) receptor agonist.

The metabotropic glutamate receptor 7 allosteric modulator AMN082: a monoaminergic agent in disguise?

Metabotropic glutamate receptor 7 (mGluR7) remains the most elusive of the eight known mGluRs primarily because of the limited availability of tool compounds to interrogate its potential therapeutic utility. The discovery of N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) as the first orally active, brain-penetrable, mGluR7-selective allosteric agonist by Mitsukawa and colleagues (Proc Natl Acad Sci USA 102:18712-18717, 2005) provides a means to investigate this receptor system directly. AMN082 demonstrates mGluR7 agonist activity in vitro and interestingly has a behavioral profile that supports utility across a broad spectrum of psychiatric disorders including anxiety and depression. The present studies were conducted to extend the in vitro and in vivo characterization of AMN082 by evaluating its pharmacokinetic and metabolite profile. Profiling of AMN082 in rat liver microsomes revealed rapid metabolism (t(1/2) < 1 min) to a major metabolite, N-benzhydrylethane-1,2-diamine (Met-1). In vitro selectivity profiling of Met-1 demonstrated physiologically relevant transporter binding affinity at serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) (323, 3020, and 3410 nM, respectively); whereas the parent compound AMN082 had appreciable affinity at NET (1385 nM). AMN082 produced antidepressant-like activity and receptor occupancy at SERT up to 4 h postdose, a time point at which AMN082 is significantly reduced in brain and plasma while the concentration of Met-1 continues to increase in brain. Acute Met-1 administration produced antidepressant-like activity as would be expected from its in vitro profile as a mixed SERT, NET, DAT inhibitor. Taken together, these data suggest that the reported in vivo actions of AMN082 should be interpreted with caution, because they may involve other mechanisms in addition to mGluR7.

Identification of 3-sulfonylindazole derivatives as potent and selective 5-HT(6) antagonists.

As part of our efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT(6) receptor in order to identify potent and selective ligands for this purpose. Herein we report the identification of a novel series of 3-sulfonylindazole derivatives with acyclic amino side chains as potent and selective 5-HT(6) antagonists. The synthesis and detailed SAR of this class of compounds are reported.

Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer.

Pancreas ductal adenocarcinoma (PDAC) is a highly lethal cancer that typically presents as advanced, unresectable disease. This invasive tendency, coupled with intrinsic resistance to standard therapies and genome instability, are major contributors to poor long-term survival. The genetic elements governing the invasive propensity of PDAC have not been well elucidated. Here, in the course of validating resident genes in highly recurrent and focal amplifications in PDAC, we have identified Rio Kinase 3 (RIOK3) as an amplified gene that alters cytoskeletal architecture as well as promotes pancreatic ductal cell migration and invasion. We determined that RIOK3 promotes its invasive activities through activation of the small G protein, Rac. This genomic and functional link to Rac signaling prompted a genome wide survey of other components of the Rho family network, revealing p21 Activated Kinase 4 (PAK4) as another amplified gene in PDAC tumors and cell lines. Like RIOK3, PAK4 promotes pancreas ductal cell motility and invasion. Together, the genomic and functional profiles establish the Rho family GTP-binding proteins as integral to the hallmark invasive nature of this lethal disease.

The treatment gap: The missed opportunities for osteoporosis therapy.

Despite substantial advances in delineation of the epidemiology, pathophysiology, risk assessment and treatment of osteoporosis over the last three decades, a substantial proportion of men and women at high risk of fracture remain untreated - the so-called "treatment gap". This review summarises the important patient-, physician- and policyrelated causes of this treatment gap, before discussing in greater detail: (a) the evidence base for the efficacy of bisphosphonates in osteoporosis; (b) recent evidence relating to the adverse effects of this widely used therapeutic class, most notably atypical femoral fracture and osteonecrosis of the jaw; (c) available strategies to improve both secondary and primary prevention pathways for the management of this disorder.

Preclinical characterization of BRL 44408: antidepressant- and analgesic-like activity through selective alpha2A-adrenoceptor antagonism.

Biogenic amines such as norepinephrine, dopamine, and serotonin play a well-described role in the treatment of mood disorders and some types of pain. As alpha2A-adrenoceptors regulate the release of these neurotransmitters, we examined the therapeutic potential of BRL 44408, a potent (Ki=8.5 nM) and selective (>50-fold) alpha2A-adrenoceptor antagonist (K(B)=7.9 nM). In rats, BRL 44408 penetrated the central nervous system resulting in peak brain and plasma concentrations of 586 ng/g and 1124 ng/ml, respectively. In a pharmacodynamic assay, pretreatment with BRL 44408 to rats responding under a fixed-ratio 30 operant response paradigm resulted in a rightward shift of the clonidine dose-response curve, an effect indicative of alpha2-adrenoceptor antagonism in vivo. Consistent with presynaptic autoreceptor antagonism and tonic regulation of neurotransmitter release, acute administration of BRL 44408 elevated extracellular concentrations of norepinephrine and dopamine, but not serotonin, in the medial prefrontal cortex. Additionally, BRL 44408, probably by inhibiting alpha2A heteroceptors, produced a significant increase in cortical levels of acetylcholine. In the forced swim test and schedule-induced polydipsia assay, BRL 44408 produced an antidepressant-like response by dose-dependently decreasing immobility time and adjunctive water intake, respectively, while in a model of visceral pain, BRL 44408 exhibited analgesic activity by decreasing para-phenylquinone (PPQ)-induced abdominal stretching. Finally, BRL 44408 did not produce deficits in overall motor coordination nor alter general locomotor activity. This preclinical characterization of the neurochemical and behavioural profile of BRL 44408 suggests that selective antagonism of alpha2A-adrenoceptors may represent an effective treatment strategy for mood disorders and visceral pain.

Potent dihydroquinolinone dopamine D2 partial agonist/serotonin reuptake inhibitors for the treatment of schizophrenia.

A dihydroquinolinone moiety was found to be a potent serotonin reuptake inhibitor pharmacophore when combined with certain amines. This fragment was coupled with selected D(2) ligands to prepare a series of dual acting compounds with attractive in vitro profiles as dopamine D(2) partial agonists and serotonin reuptake inhibitors. Structure-activity studies revealed that the linker plays a key role in contributing to D(2) affinity, function, and SRI activity.

Identification of a novel series of 3-piperidinyl-5-sulfonylindazoles as potent 5-HT6 ligands.

Cognitive dysfunction is a characteristic of various forms of dementia such as Alzheimer's disease (AD) and a core feature of schizophrenia. As part of our continuing efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT(6) receptor-one of the emerging therapeutic targets in this area. Herein, we report the identification of a novel series of 3-piperidinyl-5-sulfonylindazole derivatives as potent 5-HT(6) antagonists. The synthesis and SAR of this class of compounds are reported.

1-Sulfonylindazoles as potent and selective 5-HT6 ligands.

As part of our continuing efforts to identify therapeutics for CNS diseases, such as schizophrenia and Alzheimer's disease (AD), we have been focused on the 5-HT(6) receptor in an attempt to identify ligands as a potential treatment for cognitive dysfunction. Herein we report the identification of a novel series of 1-sulfonylindazole derivatives as potent and selective 5-HT(6) antagonists. The synthesis and SAR of this class of compounds are reported. Several potent compounds in both binding and cyclase functional assays also display good selectivity, microsomal stability, solubility, and brain penetration as well as low cytochrome P450 inhibition. One compound exemplified in this series showed 24% oral bioavailability and in vivo efficacy in a NOR cognition model at 10mg/kg following an oral administration in rats.