Operationalizing a fisheries social-ecological system through a Bayesian belief network reveals hotspots for its adaptive capacity in the southern North sea.

Fisheries social-ecological systems (SES) in the North Sea region confront multifaceted challenges stemming from environmental changes, offshore wind farm expansion, and marine protected area establishment. In this paper, we demonstrate the utility of a Bayesian Belief Network (BN) approach in comprehensively capturing and assessing the intricate spatial dynamics within the German plaice-related fisheries SES. The BN integrates ecological, economic, and socio-cultural factors to generate high-resolution maps of profitability and adaptive capacity potential (ACP) as prospective management targets. Our analysis of future scenarios, delineating changes in spatial constraints, economics, and socio-cultural aspects, identifies factors that will exert significant influence on this fisheries SES in the near future. These include the loss of fishing grounds due to the installation of offshore wind farms and marine protected areas, as well as reduced plaice landings due to climate change. The identified ACP hotspots hold the potential to guide the development of localized management strategies and sustainable planning efforts by highlighting the consequences of management decisions. Our findings emphasize the need to consider detailed spatial dynamics of fisheries SES within marine spatial planning (MSP) and illustrate how this information may assist decision-makers and practitioners in area prioritization. We, therefore, propose adopting the concept of fisheries SES within broader integrated management approaches to foster sustainable development of inherently dynamic SES in a rapidly evolving marine environment.

Evaluation of pain-alleviating strategies during allergy shots (subcutaneous immunotherapy): a randomized controlled pilot study.

Summary: Background. Subcutaneous immunotherapy (SCIT) is a potential disease-modifying therapy effective for treatment of various allergic disorders. Pain and fear are common concerns of children, which can pose stress and result in negative experiences. The purpose of this study was to evaluate and compare the effectiveness of three marketed distraction devices and ethyl chloride spray (a routinely used topical anesthetic agent for painful procedures), the current clinical standard of care in reducing the perception of needle pain during SCIT administration in children. Methods. 40 children, aged 4-17 years, receiving SCIT with use of one of three alternative pain therapies or with standard practice were enrolled. Participants were randomly assigned to one of the pain-modifying interventions. The three interventional groups were ShotBlocker® (Bionix, Toledo, OH, USA), Buzzy® I (Pain Care Labs, Atlanta, GA, USA) (vibration only), and Buzzy® II (vibration with ice). Control group was ethyl chloride spray. The study consisted of two visits during SCIT administration process. Results. Of these 40 children, 12 received the ShotBlocker, 8 received the Buzzy I, 11 received the Buzzy II, and 9 received ethyl chloride spray (control group). Conclusions. There were no significant differences found between each of the distraction devices and between the control group. Type II error/false negative finding cannot be ruled out because of a small sample. Therefore, we cannot conclude that no true difference exists between each distraction device and the control group simply because of occurrence of a non-significant P-value in our study.

Evaluation of marine spatial planning requires fit for purpose monitoring strategies.

Marine spatial planning (MSP) has rapidly become the most widely used integrated, place-based management approach in the marine environment. Monitoring and evaluation of MSP is key to inform best practices, adaptive management and plan iteration. While standardised evaluation frameworks cannot be readily applied, accounting for evaluation essentials such as the definition of evaluation objectives, indicators and stakeholder engagement of stakeholders is a prerequisite for meaningful evaluation outcomes. By way of a literature review and eleven practical MSP case studies, we analysed present day trends in evaluation approaches and unravelled the adoption of evaluation essentials for three categories for monitoring and evaluation for plan making, plan outcomes, and policy implementation. We found that at a global scale the focus of MSP evaluation has shifted over the past decade from evaluating predominantly plan outcomes towards the evaluation of plan making. Independent of the scope of the evaluation, evaluation approaches varied greatly from formal and structured processes, building for instance on MSP goals and objectives, to informal processes based on stakeholder interviews. We noted a trend in the adoption of formalised approaches where MSP evaluations have increasingly become linked to MSP policy goals and objectives. However, the enhanced use of MSP objectives and indicators did not result in a more straightforward reporting of outcomes, e.g. such as the achievement of specific MSP objectives. Overall, we found weak linkages between defined MSP objectives, indicators and available monitoring data. While the apparent shift towards a focus on objectives is promising, we highlight the need of fit-for-purpose monitoring data to enable effective evaluation of those objectives. Hence, effective MSP and adaptive management processes require customised and concurrent monitoring and evaluation strategies and procedures. We argue that evaluation processes would also benefit from a better understanding of the general environmental, socio-economic and socio-cultural effects of MSP. Therefore, to understand better environmental effects of MSP, we praise that forthcoming MSP processes need to deepen the understanding and considerations of cause-effect pathways between human activities and changes of ecosystem state through the adoption of targeted cumulative effects assessments.

Stent thrombogenicity early in high-risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings.

BACKGROUND: Stent thrombosis is a lethal complication of endovascular intervention. Concern has been raised about the inherent risk associated with specific stent designs and drug-eluting coatings, yet clinical and animal support is equivocal. METHODS AND RESULTS: We examined whether drug-eluting coatings are inherently thrombogenic and if the response to these materials was determined to a greater degree by stent design and deployment with custom-built stents. Drug/polymer coatings uniformly reduce rather than increase thrombogenicity relative to matched bare metal counterparts (0.65-fold; P=0.011). Thick-strutted (162 µm) stents were 1.5-fold more thrombogenic than otherwise identical thin-strutted (81 µm) devices in ex vivo flow loops (P<0.001), commensurate with 1.6-fold greater thrombus coverage 3 days after implantation in porcine coronary arteries (P=0.004). When bare metal stents were deployed in malapposed or overlapping configurations, thrombogenicity increased compared with apposed, length-matched controls (1.58-fold, P=0.001; and 2.32-fold, P<0.001). The thrombogenicity of polymer-coated stents with thin struts was lowest in all configurations and remained insensitive to incomplete deployment. Computational modeling-based predictions of stent-induced flow derangements correlated with spatial distribution of formed clots. CONCLUSIONS: Contrary to popular perception, drug/polymer coatings do not inherently increase acute stent clotting; they reduce thrombosis. However, strut dimensions and positioning relative to the vessel wall are critical factors in modulating stent thrombogenicity. Optimal stent geometries and surfaces, as demonstrated with thin stent struts, help reduce the potential for thrombosis despite complex stent configurations and variability in deployment.

Allosteric modulators of the δ GABAA receptor subtype demonstrate a therapeutic effect in morphine-antinociceptive tolerance and withdrawal in mice.

The present study evaluated the effects of compounds targeting extrasynaptic δ subunit-containing γ-aminobutyric acid type A receptors (δ*-GABAARs) to interrogate the role of tonic inhibition in the development of antinociceptive tolerance caused by repeated morphine administration. We investigated the effect of subchronic or acute treatment with non-steroidal positive allosteric modulators (PAMs) of δ*-GABAARs, such as 2-261, on the morphine-antinociceptive tolerance. Mice were treated twice daily with morphine for 9 days and antinociception was measured using the hot water tail immersion test. Co-treatment with 2-261 and morphine prevented morphine-antinociceptive tolerance and acute administration of 2-261 on day 9 was sufficient to reverse the tolerance. Other compounds with activity at δ*-GABAARs also reversed morphine tolerance, whereas an enaminone that lacked activity at δ*-GABAARs did not. Acute administration of 2-261 did not cause an additive or synergistic antinociceptive effect when combined with an acute submaximal dose of morphine. We then used Cre/LoxP recombination to generate GABAA δ-subunit knockout mice to corroborate the pharmacological results. Observations of male δ-knockout mice demonstrated that the δ*-GABAARs was necessary for 2-261 modulation of both analgesic tolerance and somatic withdrawal symptoms produced by subchronic morphine. While female mice still benefited from the positive effects of 2-261, the δ-subunit was not necessary for these effects, highlighting a distinction of the different pathways that could have implications for some of the sex-related differences seen in human opioid-induced outcomes. Consequently, subtype-specific allosteric modulators of GABAARs may warrant further investigation as pharmacological targets to manage tolerance and withdrawal from opioids.

Photolysis of a caged peptide reveals rapid action of N-ethylmaleimide sensitive factor before neurotransmitter release.

The time at which the N-ethylmaleimide-sensitive factor (NSF) acts during synaptic vesicle (SV) trafficking was identified by time-controlled perturbation of NSF function with a photoactivatable inhibitory peptide. Photolysis of this caged peptide in the squid giant presynaptic terminal caused an abrupt (0.2 s) slowing of the kinetics of the postsynaptic current (PSC) and a more gradual (2-3 s) reduction in PSC amplitude. Based on the rapid rate of these inhibitory effects relative to the speed of SV recycling, we conclude that NSF functions in reactions that immediately precede neurotransmitter release. Our results indicate the locus of SNARE protein recycling in presynaptic terminals and reveal NSF as a potential target for rapid regulation of transmitter release.

Socio-ecological vulnerability to tipping points: A review of empirical approaches and their use for marine management.

Sustainability in the provision of ecosystem services requires understanding of the vulnerability of social-ecological systems (SES) to tipping points (TPs). Assessing SES vulnerability to abrupt ecosystem state changes remains challenging, however, because frameworks do not operationally link ecological, socio-economic and cultural elements of the SES. We conducted a targeted literature review on empirical assessments of SES and TPs in the marine realm and their use in ecosystem-based management. Our results revealed a plurality of terminologies, definitions and concepts that hampers practical operationalisation of these concepts. Furthermore, we found a striking lack of socio-cultural aspects in SES vulnerability assessments, possibly because of a lack of involvement of stakeholders and interest groups. We propose guiding principles for assessing vulnerability to TPs that build on participative approaches and prioritise the connectivity between SES components by accounting for component linkages, cascading effects and feedback processes.

Single Portion Packaging and the Use of User Test Protocols to Determine Patient Accessibility.

In 2015, the UK National Health Service (NHS) established a taskforce to review single portion food and beverage packaging, which has been identified as a potential challenge to users in hospitals. Hence, a study was undertaken to determine the suitability and accessibility of the current single portion packs. The packaging was assessed using ISO 17480 (Guidelines for Accessible Packaging), Annex D. The standard determines a pass or fail of packaging opening asking a panel 20 older adults to open a pack. A pack is recorded as a failure if within the 20 people cohort, there is an example of pack being unable to be opened within the time limit (defined as 1 minute) or the overall satisfaction score ranks below 3 on a 5-point Likert scale. Ten standard single portion packaging items were randomly selected for testing. The packs were chosen to reflect a broad range of food and beverage and packaging types. The results showed that the standard provided useful assessment data, identifying that 70% of the packs were so poorly designed that they failed to pass the standard, with 50% of the packs having examples that were unopenable by the participants, whilst a further 20% rated poorly for satisfaction.

Chemical two-photon uncaging: a novel approach to mapping glutamate receptors.

Functional mapping of neurotransmitter receptors requires rapid and localized application of transmitter. The usefulness of caged glutamate for this purpose has been limited, because photolysis by unfocused light above and below the target cell limits depth resolution. This problem is eliminated by using a double-caged glutamate that requires absorption of two photons for conversion to active glutamate, resulting in a substantial improvement in spatial resolution over conventional caged glutamate. This method was used to map the distribution of glutamate receptors on hippocampal pyramidal neurons. A higher density of AMPA receptors was found on distal apical dendrites than on basal or primary apical dendrites, suggesting that synaptic efficacy is locally heterogeneous. Such "chemical two-photon uncaging" offers a simple, general, and economical strategy for spatially localized photolysis of caged compounds.

Monitoring presynaptic calcium dynamics in projection fibers by in vivo loading of a novel calcium indicator.

Fluorometric calcium measurements have revealed presynaptic residual calcium (Ca(res)) to be an important regulator of synaptic strength. However, in the mammalian brain, it has not been possible to monitor Ca(res) in fibers that project from one brain region to another. Here, we label neuronal projections by injecting dextran-conjugated calcium indicators into brain nuclei in vivo. Currently available dextran conjugates distort Ca(res) due to their high affinity for calcium. Therefore, we synthesized a low-affinity indicator, fluo-4 dextran, that can more accurately measure the amplitude and time course of Ca(res). We then demonstrate the utility of fluo-4 dextran by measuring Ca(res) at climbing fiber presynaptic terminals. This method promises to facilitate the study of many synapses in the mammalian CNS, both in brain slices and in vivo.

IL-27 amplifies cytokine responses to Gram-negative bacterial products and Salmonella typhimurium infection.

Cytokine responses from monocytes and macrophages exposed to bacteria are of particular importance in innate immunity. Focusing on the impact of the immunoregulatory cytokine interleukin (IL)-27 on control of innate immune system responses, we examined human immune responses to bacterial products and bacterial infection by E. coli and S. typhimurium. Since the effect of IL-27 treatment in human myeloid cells infected with bacteria is understudied, we treated human monocytes and macrophages with IL-27 and either LPS, flagellin, or bacteria, to investigate the effect on inflammatory signaling and cytokine responses. We determined that simultaneous stimulation with IL-27 and LPS derived from E. coli or S. typhimurium resulted in enhanced IL-12p40, TNF-α, and IL-6 expression compared to that by LPS alone. To elucidate if IL-27 manipulated the cellular response to infection with bacteria, we infected IL-27 treated human macrophages with S. typhimurium. While IL-27 did not affect susceptibility to S. typhimurium infection or S. typhimurium-induced cell death, IL-27 significantly enhanced proinflammatory cytokine production in infected cells. Taken together, we highlight a role for IL-27 in modulating innate immune responses to bacterial infection.

Ultra-hydrophilic stent platforms promote early vascular healing and minimise late tissue response: a potential alternative to second-generation drug-eluting stents.

AIMS: Simple surface modifications can enhance coronary stent performance. Ultra-hydrophilic surface (UHS) treatment of contemporary bare metal stents (BMS) was assessed in vivo to verify whether such stents can provide long-term efficacy comparable to second-generation drug-eluting stents (DES) while promoting healing comparably to BMS. METHODS AND RESULTS: UHS-treated BMS, untreated BMS and corresponding DES were tested for three commercial platforms. A thirty-day and a 90-day porcine coronary model were used to characterise late tissue response. Three-day porcine coronary and seven-day rabbit iliac models were used for early healing assessment. In porcine coronary arteries, hydrophilic treatment reduced intimal hyperplasia relative to the BMS and corresponding DES platforms (1.5-fold to threefold reduction in 30-day angiographic and histological stenosis; p<0.04). Endothelialisation was similar on UHS-treated BMS and untreated BMS, both in swine and rabbit models, and lower on DES. Elevation in thrombotic indices was infrequent (never observed with UHS, rare with BMS, most often with DES), but, when present, correlated with reduced endothelialisation (p<0.01). CONCLUSIONS: Ultra-hydrophilic surface treatment of contemporary stents conferred good healing while moderating neointimal and thrombotic responses. Such surfaces may offer safe alternatives to DES, particularly when rapid healing and short dual antiplatelet therapy (DAPT) are crucial.

Differences in bone density, body composition, physical activity, and diet between child gymnasts and untrained children 7-8 years of age.

Strategies that enhance the acquisition of bone mass may be protective against osteoporosis. BMD was compared in 20 artistic gymnasts (10 boys; 10 girls) and 20 untrained children ages 7-8 years. Higher regional values of BMD were observed in female gymnasts than untrained girls. If retained to adulthood, this higher BMD may protect skeletal integrity in later life. Strategies that enhance the acquisition of bone mass in children may assist with the prevention of osteoporosis. This study explored the effects of regular high-impact and weight-bearing activity before the age of 7 years on total and regional bone mineral density (BMD). Twenty artistic gymnasts (10 boys and 10 girls) and 20 untrained children, 7-8 years of age, were recruited. The untrained children were matched to gymnasts by sex, height, weight, and age. Female gymnasts trained 8-10 h per week and had trained regularly for 3-4 years. Male gymnasts trained 4-6 h per week and had trained for 1-2 years. Measurements of bone mineral density were made using DXA for total body BMD (TBBMD); lumbar spine, both areal (aSBMD) and volumetric (vSBMD); total spine; pelvis; arms; and legs. Significant mean differences (8-10%) in aSBMD, vSBMD, arm BMD, and TBBMD were observed between female gymnasts and untrained girls (p < 0.05: aSBMD, vSBMD, and TBBMD body mass (BM); p < 0.01: arm BMD). A nonsignificant trend toward a higher TBBMD/BM and arm BMD was observed in male gymnasts compared with untrained boys. Trends toward a higher BMD within the pelvis, legs, and total spine were also observed in gymnasts. There were no differences in total and regional BMD between untrained boys and untrained girls. The results suggest that gymnastics training before the age of 7 years enhances the acquisition of bone mass at selected skeletal sites. The magnitude of this enhancement seems to be linked to the cumulative volume of such training. If retained during adolescence and young adulthood, a surfeit of bone acquired through high-impact and weight-bearing activity in early childhood may protect skeletal integrity in later life.

Measuring zinc in living cells. A new generation of sensitive and selective fluorescent probes.

New fluorescent indicators with nanomolar to micromolar affinities for Zn(2+) have been synthesized in wavelengths from UV to the far red. The UV light-excited indicators are ratiometric. The visible wavelength indicators are non-ratiometric and exhibit large and pH-independent fluorescence increases with increasing zinc concentrations, with little to no sensitivity to physiologically relevant Ca(2+) concentrations. Experiments in neuronal and non-neuronal cell cultures show the new indicators to retain their sensitivity to and selectivity for zinc after conversion to cell-permeable forms.

Chemical and physiological characterization of fluo-4 Ca(2+)-indicator dyes.

We have developed fluo-4, a new fluorescent dye for quantifying cellular Ca2+ concentrations in the 100 nM to 1 microM range. Fluo-4 is similar in structure and spectral properties to the widely used fluorescent Ca(2+)-indicator dye, fluo-3, but it has certain advantages over fluo-3. Due to its greater absorption near 488 nm, fluo-4 offers substantially brighter fluorescence emission when used with excitation by argon-ion laser or other sources in conjunction with the standard fluorescein filter set. In vitro, fluo-4 exhibited high fluorescence emission, a high rate of cell permeation, and a large dynamic range for reporting [Ca2+] around a Kd(Ca2+) of 345 nM. We have also developed several Ca(2+)-indicators related to fluo-4 having lower affinities for Ca2+ that are useful in cellular studies requiring quantification of higher [Ca2+]. In a variety of physiological studies of live cells, fluo-4 labeled cells more brightly than did fluo-3, when challenged with procedures designed to elevate calcium levels. Fluo-4 is well suited for photometric and imaging applications that make use of confocal laser scanning microscopy, flow cytometry, or spectrofluorometry, or in fluorometric high-throughput microplate screening assays. Because of its higher fluorescence emission intensity, fluo-4 can be used at lower intracellular concentrations, making its use a less invasive practice.

Anticonvulsant steroids and the GABA/benzodiazepine receptor-chloride ionophore complex.

The ability of steroids to influence brain excitability is well documented. Certain 3 alpha-hydroxylated pregnanes are known to possess anticonvulsant and sedative-hypnotic/anesthetic properties. It has been observed that the seizure susceptibility in menstruating women with catamenial epilepsy appears to be correlated with changes in ovarian steroid levels. However, the underlying mechanism of these steroid influences on brain activity has only been recently revealed by pharmacological studies. These studies have provided compelling evidence for the presence of a novel steroid recognition site on the GABAA-benzodiazepine receptor complex (GBRC). Steroids may interact with this site with high affinity and stereospecificity to enhance chloride channel conductance in a manner similar to that produced by benzodiazepines (BZs) or barbiturates. The existence of such a steroid site on the GBRC is further supported by recent experiments involving the transfection of GABAA receptor cDNAs into a human embryonic kidney cell line. Based on the knowledge of the structure-activity requirements for the interaction of steroids with this novel recognition site, it is conceivable that the development of new anticonvulsant steroids with high therapeutic indices can be achieved.

Steroid modulation of the GABA/benzodiazepine receptor-linked chloride ionophore.

Recent findings suggest that steroids with sedative-hypnotic properties interact specifically with the gamma-aminobutyric acidA/benzodiazepine receptor-chloride ionophore complex (GBRC). They show positive heterotropic cooperativity by allosterically enhancing the binding of GABA agonists and the clinically useful benzodiazepines (BZs) to their respective recognition sites. These steroids have stringent structural requirements for activity at the GBRC, with the essential requirements for high potency being a 3 alpha-hydroxyl group and a 5 alpha-reduced A-ring. Some of these steroids are naturally occurring metabolites of progesterone and deoxycorticosterone and have nanomolar potencies as potentiators of chloride channel conductance. These 3 alpha-hydroxylated, 5 alpha-reduced steroids do not act through any known sites on the GBRC. Thus, the exact site and mechanism of action remain to be determined. Together with the observation that physiological levels of these metabolites are sufficient to influence the function of the GBRC, the evidence clearly suggests a role for these steroids in the normal regulation of brain excitability by potentiating the postsynaptic effects of gamma-aminobutyric acid (GABA). Pharmacological studies of the GBRC-active steroids show that they possess anxiolytic and anticonvulsant activities. The potential therapeutic application of these steroids in the treatment of mood disorders and catamenial exacerbation of seizures associated with the menstrual cycle is discussed. Collectively, the evidence from the studies of these steroids imply that another mechanism by which the endocrine system influences brain function has been identified. Its characterization will provide important insight into how steroids modulate brain excitability under normal and pathophysiological states.

Redox-dependent trafficking of 2,3,4,5, 6-pentafluorodihydrotetramethylrosamine, a novel fluorogenic indicator of cellular oxidative activity.

The trafficking of 2,3,4,5,6-pentafluorodihydrotetramethylrosamine (PF-H(2)TMRos, also known as RedoxSensor Red), a new fluorogenic indicator for oxidative activity, was evaluated in a contact-inhibited cell line, normal rat kidney fibroblast (NRK-49F), using quantitative fluorescence microscopy. After cells were incubated with 1-5 microM dye at 37 degrees C for 10 to 30 min, fluorescent staining of its oxidized product (PF-TMRos) distributed in mitochondria and/or lysosomes. This distribution pattern varied depending on the proliferation state of cells. In proliferating cells, PF-H(2)TMRos was internalized through a nonendocytic pathway, then oxidized in the cytosol, followed by immediate targeting to active mitochondria, resulting in fluorescent staining in this organelle. Photo-oxidation experiments demonstrated that PF-H(2)TMRos is not directly transported to mitochondria. On the contrary, in contact-inhibited cells whose proliferation is inhibited, PF-H(2)TMRos enters cells and is transported to lysosomes before it is oxidized. This results in lysosomal rather than mitochondrial staining. In both proliferating and quiescent cell states, subcellular distribution of the oxidized dye PF-TMRos can be altered by treatment with an oxidant (hydrogen peroxide) or an antioxidant (N-acetyl-L-cysteine), indicating a regulatory relationship between cell proliferation and oxidative activity. In solution assay, this probe can be oxidized by a broad spectrum of oxidizing species including horseradish peroxidase, hydrogen peroxide and horseradish peroxidase, cytochrome c, cytochrome c and hydrogen peroxide, superoxide and hydrogen peroxide, nitric oxide (or nitrite), peroxynitrite, and lipid hydroperoxide. Based on its subcellular distribution and its oxidation by a broad range of oxidizing species, PF-H(2)TMRos is demonstrated to be a novel indicator for cellular oxidative stresses.

Modulation of human recombinant GABAA receptors by pregnanediols.

Utilising two point voltage-clamp techniques on Xenopus laevis oocytes expressing human (alpha 1 beta 1 gamma 2L) recombinant GABAA receptors, the GABA modulatory actions of six naturally occurring neurosteroids have been determined and compared with those of known positive allosteric modulators. The anaesthetic steroids 5 alpha- and 5 beta-pregnan-3 alpha-ol-20-one produced a concentration-dependent enhancement of the GABA-evoked current. The maximal enhancement of the agonist-induced response produced by these steroids was intermediate between that of pentobarbitone and diazepam, but much greater than that caused by bretazenil. For both the 5 alpha and 5 beta steroid a reduction of the 20 ketone group to form either the corresponding 20 alpha or 20 beta hydroxy steroid produced, in all cases, a reduction in potency and a decrease in the maximal effect. The relationship of steroid structure to these two parameters is considered. The influence of the alpha subtype (alpha x beta 1 gamma 2L, where x = 1, 2 or 3) for the behaviourally active 5 alpha-pregnan-3 alpha,20 alpha-diol is also determined. Although the maximal effect of the steroid is not influenced by the alpha subtype, the alpha 2-containing receptor exhibits a modest decrease (approximately 6-fold) in potency compared to alpha 1- and alpha 3-containing receptors. The results described here are discussed in relation to the distinct behavioural actions of the neurosteroids.

10,5-(Iminomethano)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and derivatives. Potent PCP receptor ligands.

IDDC (3, 10,5-(iminomethano)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene++ +) and a series of substituted derivatives were synthesized and evaluated in vitro for their ability to displace tritiated MK-801 ([3H]-2) from its specific binding site in guinea pig brain homogenate. Substitution at the 3-position of 3 with bromine, chlorine, and fluorine led to increased binding affinity. In contrast, substitution of donor groups at the 3-position gave decreased binding affinities, as did all substitutions at the 7-position and on nitrogen. Where racemic mixtures were resolved, the (+)-optical antipodes were more active than their enantiomers or racemates. The most active ligand found in this study was (+)-13e (IC50 = 15.5 +/- 4.5 nM). The affinity of (+)-13e for the PCP receptor makes it among the most potent ligands known. In vitro neuroprotection was demonstrated by 3, (+)-3, and (+)-6 (N-Me-IDDC) against glutamate-induced cell death in rat hippocampal cells.