Design, Synthesis, and Preliminary Evaluation of a Potential Synthetic Opioid Rescue Agent

BACKGROUND: One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fully fentanyl-induced respiratory depression, rendering this treatment inadequate. To combat this synthetic opioid overdose crisis, this research aims at identifying a novel opioid reversal agent with enhanced efficacy towards fentanyl and other synthetic opioids. METHODS: A series of naltrexone analogues were characterized for their ability to antagonize the effects of fentanyl in vitro utilizing a modified forskolin-induced cAMP accumulation assay. Lead analogue 29 was chosen to undergo further PK studies, followed by in vivo pharmacological analysis to determine its ability to antagonize opioid-induced antinociception in the hot plate assay. RESULTS: A series of potent MOR antagonists were identified, including the highly potent analogue 29 (IC50 = 2.06 nM). Follow-up PK studies revealed 29 to possess near 100% bioavailability following IP administration. Brain concentrations of 29 surpassed plasma concentrations, with an apparent terminal half-life of ~ 80 min in mice. In the hot plate assay, 29 dose-dependently (0.01–0.1 mg/kg; IP) and fully antagonized the antinociception induced by oxycodone (5.6 mg/kg; IP). Furthermore, the dose of 29 that is fully effective in preventing oxycodone-induced antinociception (0.1 mg/kg) was ineffective against locomotor deficits caused by the KOR agonist U50,488. CONCLUSIONS: Methods have been developed that have utility to identify enhanced rescue agents for the treatment of OIRD. Analogue 29, possessing potent MOR antagonist activity in vitro and in vivo, provides a promising lead in our search for an enhanced synthetic opioid rescue agent

Mediterranean sea turtles: Current knowledge and priorities for conservation and research

This is the final version. Available on open access from Inter Research via the DOI in this recordThe available information regarding the 2 sea turtle species breeding in the Mediterranean (loggerhead turtle Caretta caretta and green turtle Chelonia mydas) is reviewed, including biometrics and morphology, identification of breeding and foraging areas, ecology and behaviour, abundance and trends, population structure and dynamics, anthropogenic threats and conservation measures. Although a large body of knowledge has been generated, research efforts have been inconsistently allocated across geographic areas, species and topics. Significant gaps still exist, ranging from the most fundamental aspects, such as the distribution of major nesting sites and the total number of clutches laid annually in the region, to more specific topics like age at maturity, survival rates and behavioural ecology, especially for certain areas (e.g. south-eastern Mediterranean). These gaps are particularly marked for the green turtle. The recent positive trends of nest counts at some nesting sites may be the result of the cessation of past exploitation and decades of conservation measures on land, both in the form of national regulations and of continued active protection of clutches. Therefore, the current status should be considered as dependent on such ongoing conservation efforts. Mitigation of incidental catch in fisheries, the main anthropogenic threat at sea, is still in its infancy. From the analysis of the present status a comprehensive list of re search and conservation priorities is proposed.C.C. is supported by the project CTM2013-48163 of the Spanish Ministry of Economy and Competitivity. The Cyprus Wildlife Society (CWS) acknowledges the financial support of the Department of Fisheries and Marine Research of the Government to the CWS for the implementation of the Turtle Conservation Project in the period 2010−2016 and for all its assistance to the Society in previous years. J.T. is supported by project Prometeo II (2015-018) of the Generalitat Valenciana and projects MEDSEALITTER-INTERREG and INDICIT of the European Union

The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments

This work is licensed under a Creative Commons Attribution 4.0 International License.(−)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). “Body” and “tail” interactions with opioid receptors (a subset of Portoghese’s message-address theory) were used for molecular modeling and simulations, where the “address” can be considered the “body” of the hydromorphone molecule and the “message” delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/μ potency ratio of 1.2 in the ([35S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.NIDA grant P30 DA13429NIDA grant DA039997NIDA grant DA018151NIDA grant DA035857NIDA grant DA047574NIH Intramural Research Programs of the National Institute on Drug AbuseNational Institute of Alcohol Abuse and AlcoholismNIH Intramural Research Programs of the National Institute on Drug AbuseNIH Intramural Research Program through the Center for Information TechnologyNIH Intramural Research Programs of the National Institute on Drug Abus

Recoilless Resonant Absorption of Monochromatic Neutrino Beam for Measuring Delta m^2_{31} and theta_{13}

We discuss, in the context of precision measurement of Delta m^2_{31} and theta_{13}, physics capabilities enabled by the recoilless resonant absorption of monochromatic antineutrino beam enhanced by the M\"ossbauer effect recently proposed by Raghavan. Under the assumption of small relative systematic error of a few tenth of percent level between measurement at different detector locations, we give analytical and numerical estimates of the sensitivities to Delta m^2_{31} and sin^2 2theta_{13}. The accuracies of determination of them are enormous; The fractional uncertainty in Delta m^2_{31} achievable by 10 point measurement is 0.6% (2.4%) for sin^2 2theta_{13} = 0.05, and the uncertainty of sin^2 2theta_{13} is 0.002 (0.008) both at 1 sigma CL with the optimistic (pessimistic) assumption of systematic error of 0.2% (1%). The former opens a new possibility of determining the neutrino mass hierarchy by comparing the measured value of Delta m^2_{31} with the one by accelerator experiments, while the latter will help resolving the theta_{23} octant degeneracy.Comment: 23 pages, 3 figures, version to appear in New Journal of Physic

New aspects of the carbonylation of allylpalladium complexes

The carbonylation of (η3-allyl)palladium(II) chloride dimer in the presence of an excess of ylide, such as Ph3PC(H)COR (R Me or Ph) (Pd:ylide = 1:5) in MeOH or EtOH, at a CO pressure of 4 atm at room temperature occurs with reduction of the palladium(II) complex to palladium metal and with formation of the corresponding alkyl 3- butenoate with a high yield. The ylide does not give rise to any carbonylation product. When the carbonylation is carried out in the presence of PPh3 (Pd : PPh3 = 1 : 2-3), there is also formation of the unsaturated ester, although in lesser amount, together with [Pd3(PPh3)n(CO)3] (n = 3 or 4) or [Pd(PPh3)3(CO)] and trans-[Pd(PPh3)2(COOR)Cl] (R = Me or Et). These products also form when the carbonylation is carried out in the presence of NEt3 or PrCOONa, in place of the ylide, and of PPh3. It has also been found that [Pd(PPh3)2Cl2] reacts in MeOH or EtOH at a CO pressure of 4 atm at ambient temperature in the presence of an excess of ylide to give the corresponding carbalkoxy complex trans-[Pd(PPh3)2(COOR)Cl]. These findings suggest that the ylide probably promotes formation of carbalkoxy species, as do NEt3 or PrCOONa because the ylide can behave as a base (pKa {reversed tilde equals}7). They are strong support for the suggestion that the carbonylation of (allyl)palladium complexes occurs via a (carbalkoxy)palladium species. © 1994

‘Does My Haltung Look Big In This?”: The Use of Social Pedagogical Theory for the Development of Ethical and Value Led Practice

The aim of this article is to set out how the use of social pedagogical Haltung can support the exploration of values and how this informs and shapes a practitioner’s direct work. Haltung is a German concept that has no direct English translation but means ‘mind set’, ‘ethos’ or ‘attitude’ (Eichsteller, 2010) and relates to an individual’s value base. Mührel’s (2008, cited in Eichsteller, 2010), sets out that a social pedagogical Haltung is based on the two concepts of empathic understanding and regard. This paper argues that the use of a social pedagogical Haltung gives practitioners a philosophical framework to support the reflection of core values and ethics held on a personal level. It also supports an understanding of how these influence practitioners and students when using ‘self’ in relationship based practice. The understanding of Haltung is important but for social pedagogical practice to be undertaken it also has to be demonstrated by actions. The reflective activity Values Alive in Practice, set out in this article, provides a tool for social workers, practitioners and students to critically explore their own values and practice and make more meaningful connections between their Haltung and their behaviours demonstrated in their everyday work. In the UK, values and standards for social work practice are set out by British Association of Social Work and Social Work England. Arguably, these have, at times, been reduced to a checklist for students and practitioners and can lack more in depth and explicit links to practice. The analysis of practice is more likely to focus on the skills and abilities of practitioners rather than the value base that underpins these. Whilst the understanding and key application of core knowledge and skills is essential for competent social work practice (Forrester et al., 2019), this article argues that it must also be supported and shaped by ethical principles. This article seeks to explore how social workers can be supported to adopt value led approaches to complex work within an outcome focussed culture

Green turtles (Chelonia mydas) foraging at Arvoredo Island in Southern Brazil: Genetic characterization and mixed stock analysis through mtDNA control region haplotypes

We analyzed mtDNA control region sequences of green turtles (Chelonia mydas) from Arvoredo Island, a foraging ground in southern Brazil, and identified eight haplotypes. Of these, CM-A8 (64%) and CM-A5 (22%) were dominant, the remainder presenting low frequencies (< 5%). Haplotype (h) and nucleotide (π) diversities were 0.5570 ± 0.0697 and 0.0021 ± 0.0016, respectively. Exact tests of differentiation and AMOVA ΦST pairwise values between the study area and eight other Atlantic foraging grounds revealed significant differences in most areas, except Ubatuba and Rocas/Noronha, in Brazil (p > 0.05). Mixed Stock Analysis, incorporating eleven Atlantic and one Mediterranean rookery as possible sources of individuals, indicated Ascension and Aves islands as the main contributing stocks to the Arvoredo aggregation (68.01% and 22.96%, respectively). These results demonstrate the extensive relationships between Arvoredo Island and other Atlantic foraging and breeding areas. Such an understanding provides a framework for establishing adequate management and conservation strategies for this endangered species