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This review summarizes research data on SARS-CoV-2 in water environments. A literature survey was conducted using the electronic databases Science Direct, Scopus, and Springer. This complete research included and discussed relevant studies that involve the (1) introduction, (2) definition and features of coronavirus, (2.1) structure and classification, (3) effects on public health, (4) transmission, (5) detection methods, (6) impact of COVID-19 on the water sector (drinking water, cycle water, surface water, wastewater), (6.5) wastewater treatment, and (7) future trends. The results show contamination of clean water sources, and community drinking water is vulnerable. Additionally, there is evidence that sputum, feces, and urine contain SARS-CoV-2, which can maintain its viability in sewage and the urban-rural water cycle to move towards seawater or freshwater; thus, the risk associated with contracting COVID-19 from contact with untreated water or inadequately treated wastewater is high. Moreover, viral loads have been detected in surface water, although the risk is lower for countries that efficiently treat their wastewater. Further investigation is immediately required to determine the persistence and mobility of SARS-CoV-2 in polluted water and sewage as well as the possible potential of disease transmission via drinking water. Conventional wastewater treatment systems have been shown to be effective in removing the virus, which plays an important role in pandemic control. Monitoring of this virus in water is extremely important as it can provide information on the prevalence and distribution of the COVID-19 pandemic in different communities as well as possible infection dynamics to prevent future outbreaks.

The addiction induced by the misuse of opioids, is not only a public health emergency but also a social and economic welfare. The main therapy is based on opioid antagonists. Oral and injectable naltrexone administration is the most widely used, presenting some inconveniences: poor patient adherence to the oral daily dosing schedule, cases of hepatitis and clinically significant liver dysfunction. This study proposes the in vitro e in vivo evaluation of anti-opioid properties of naloxone loaded-poly(lactic-co-glycolic) acid microparticles (NX-MP). In previous studies, NX-MP showed in vitro sustained naloxone release for one week at least. Our results demonstrate the in vitro efficacy of the NX-MP antagonizing for 7 days the morphine effect in SH-SY5Y cells and myenteric plexus-longitudinal muscle preparations isolated from guinea-pig ileum. The in vivo evaluation of the NX-MP was carried out in mice testing the antagonism of the antinociceptive effect of morphine. Results showed that subcutaneous administration of NX-MP blocked the morphine effect. The results of this work suggest that the subcutaneous administration of NX-MP enhances naloxone therapeutic efficacy as non-addictive medication and could be a promising alternative to naltrexone. Furthermore, the dose of NX-MP can be adapted to the patient necessities. It would be an interesting advantage to treat opioid-addiction., This research was partially funded by Universidad Complutense de Madrid Research Group (910939) and by Plan Nacional sobre Drogas, Gobierno de Espana

Plenty information exists regarding the effects of chronic stress, although few data exist on the effects of short-lasting stressors, which would mimic daily challenges. Differences in craniofacial and spinal nociception have been observed, thus those observations obtained in spinally innervated areas cannot be directly applied to the orofacial region. Although, opioids are considered amongst the most effective analgesics, their use is sometimes hampered by the constipation they induce. Thus, our aims were to study if a short-lasting stressor, forced swim stress (FSS), modifies nociception, morphine antinociception and constipation in rats. Animals were submitted to 10–20 min of FSS for three days, nociception and gastrointestinal transit were studied 24 h after the last swimming session. Nociception and morphine (0.6–5 mg/kg) antinociception were evaluated in the formalin and hypertonic saline tests in the orofacial area and limbs. Morphine-induced modifications in the GI transit were studied through radiographic techniques. Naloxone was administered, before each swimming session, to analyse the involvement of the endogenous opioid system on the effect of stress. Overall, stress did not alter nociception, although interestingly it reduced the effect of morphine in the orofacial tests and in the inflammatory phase of the formalin tests. Naloxone antagonized the effect of stress and normalized the effect of morphine. Stress did not modify the constipation induced by morphine. Opioid treatment may be less effective under a stressful situation, whilst adverse effects, such as constipation, are maintained. The prevention of stress may improve the level of opioid analgesia., This work was supported by the Ministerio de Ciencia e Innovación of Spain (MINCINN. SAF2012-40075-C02-01).

Chronic pain remains a major problem worldwide, despite the availability of various non-pharmacological and pharmacological treatment options. Therefore, new analgesics with novel mechanisms of action are needed. Monoclonal antibodies (mAbs) are directed against specific, targeted molecules involved in pain signaling and processing pathways that look to be very effective and promising as a novel therapy in pain management. Thus, there are mAbs against tumor necrosis factor (TNF), nerve growth factor (NGF), calcitonin gene-related peptide (CGRP), or interleukin-6 (IL- 6), among others, which are already recommended in the treatment of chronic pain conditions such as osteoarthritis, chronic lower back pain, migraine, or rheumatoid arthritis that are under preclinical research. This narrative review summarizes the preclinical and clinical evidence supporting the use of these agents in the treatment of chronic pain., This research received no external funding.

The serum and glucocorticoid-regulated kinase 1 (SGK1) is a widely expressed protein in the Central Nervous System (CNS), involved in regulating the activity of a wide variety of ion channels and transporters and phys- iological functions, such as neuronal excitability. SGK1.1 is a neuronal splice isoform of SGK1, expressed exclusively in the CNS, distributed in brain and cerebellum, that decreases neuronal excitability via up-regulation of M-current, linked to Kv7.2/3 potassium channels. Strategies to maintain increased SGK1.1 activity could be helpful in decreasing neuronal hyperexcitability, as occurs in neuropathic pain. Transgenic mice overexpressing SGK1.1 (B6.Tg.sgk1) offer a particularly relevant opportunity to assess the physiological involvement of this protein in nociception. Behavior and physiological nociception were evaluated in male and female B6.Tg.sgk1 and wild-type mice (B6.WT), characterizing nociceptive thresholds to different nociceptive stimuli (thermal, chemical and me- chanical), as well as the electrophysiological properties of cutaneous sensory Aδ-fibres isolated from the saphenous nerve. The acute antinociceptive effect of morphine was also evaluated. Compared with B6.WT animals, male and female B6.Tg.sgk1 mice showed increased spontaneous locomotor activity. Regarding nociception, there were no differences between transgenic and wild-type mice in heat, chemical and mechanical thresholds, but interestingly, male B6.Tg.sgk1 mice were less sensitive to cold stimulus; B6.Tg.sgk1 animals showed lower sensitivity to morphine. Electrophysiological properties of cutaneous primary afferent fibres were maintained. This is the first demonstration that the SGK1.1 isoform is involved in nociceptive modulation, offering a protective effect against noxious cold stimulus in a sexually dimorphic manner. B6.Tg.sgk1 mice offer a particularly relevant opportunity to further analyze the involvement of this protein in nociception, and studies in models of chronic, neuropathic pain are warranted., This study was supported by Ministerio de Ciencia e Innovación (SAF2012-40075-C02-01) and Fundación Española del Dolor (PI2015- FED-002 and FED research grant 2017). Authors declare no conflict of interest.

Aims: Antitumor agents, as taxanes and platinum compounds, induce peripheral neuropathies which can hamper their use for cancer treatment. The study of chemotherapy-induced neuropathies in humans is difficult because of ethical reasons, differences among administration protocols and intrinsic characteristics of patients. The aim of the present study is to compare the neuropathic signs induced by individual or combined administration of paclitaxel and oxaliplatin. Main methods: Oxaliplatin and paclitaxel were administered individually and combined to induce peripheral neuropathy in rats, sensory neuropathic signs were assessed in the hind limbs and orofacial area. The in vitro skin-saphenous nerve preparation was used to record the axonal activity of Aδ sensory neurons. Key findings: Animals treated with the combination developed mechanical allodynia in the paws and muscular hyperalgesia in the orofacial area, which was similar to that in animals treated with monotherapy, the latter also developed cold allodynia in the paws. Aδ-fibers of the rats treated with the combination were hyperexcited and presented hypersensitivity to pressure stimulation of the innervated skin, also similar to that recorded in the fibers of the animals treated with monotherapy. Significance: Our work objectively demonstrates that the combination of a platinum compound with a taxane does not worsen the development of sensorial neuropathies in rats, which is an interesting data to take into account when the combination of antitumor drugs is necessary. Co-administration of antitumor drugs is more effective in cancer treatment without increasing the risk of the disabling neuropathic side effects., This study was supported by the public institution: Ministerio de Ciencia e Innovación-MINCINN (SAF2012-40075-C02-01)

Background Cisplatin is an antineoplastic drug known to produce intense vomiting, gastric dysmotility, and peripheral neuropathy. Monosodium glutamate (MSG) is a flavor enhancer with prokinetic properties potentially useful for cancer patients under chemotherapy. Our aim was to test whether MSG may improve gastrointestinal motor dysfunction and other adverse effects induced by repeated cisplatin in rats. Methods Male Wistar rats were exposed or not to MSG (4 g L-1 ) in drinking water from week 0 to 1 week after treatment. On the first day of weeks 1-5, rats were treated with saline or cisplatin (2 mg kg-1 week-1 , ip). Gastrointestinal motility was measured by radiological methods after first and fifth administrations, as well as 1 week after treatment finalization. One week after treatment, the threshold for mechanical somatic sensitivity was recorded. Finally, samples of stomach, terminal ileum and kidneys were evaluated in sections using conventional histology. The myenteric plexus was immunohistochemically evaluated on distal colon whole-mount preparations. Key results Monosodium glutamate prevented the development of cisplatin-induced neuropathy and partially improved intestinal transit after the fifth cisplatin administration with little impact on gastric dysmotility. MSG did not improve the histological damage of gut wall, but prevented the changes induced by cisplatin in the colonic myenteric plexus. Conclusion and inferences Our results suggest that MSG can improve some dysfunctions caused by anticancer chemotherapy in the gut and other systems, associated, at least partially, with neuroprotectant effects. The potentially useful adjuvant role of this food additive to reduce chemotherapy-induced sequelae warrants further evaluation.

Synthesis and pharmacological evaluation of a new series of cannabinoid receptor antagonists of indazole ether derivatives have been performed. Pharmacological evaluation includes radioligand binding assays with [H]-CP55940 for CB1 and CB2 receptors and functional activity for cannabinoid receptors on isolated tissue. In addition, functional activity of the two synthetic cannabinoids antagonists 18 (PGN36) and 17 (PGN38) were carried out in the osteoblastic cell line MC3T3-E1 that is able to express CB2R upon osteogenic conditions. Both antagonists abolished the increase in collagen type I gene expression by the well-known inducer of bone activity, the HU308 agonist. The results of pharmacological tests have revealed that four of these derivatives behave as CB2R cannabinoid antagonists. In particular, the compounds 17 (PGN38) and 18 (PGN36) highlight as promising candidates as pharmacological tools., This work was supported from Ministerio de Ciencia e Innovación under Grant RTI2018-096100B-100, Plan Nacional de I + D + I 2013-2016, ISCIII–FEDER (FIS16/00637), Plan de Ciencia, Tecnología e Innovación 2013-2017 and 2018-2022 del Principado de Asturias (GRUPIN14-028, IDI-2018-000152), RedInRen from ISCIII (RD16/0009/0017). Natalia Carrillo López was supported by GRUPIN14-028 and IDI-2018-000152.

Loperamide is a potent mu opioid receptor agonist available over the counter to treat diarrhea. Although at therapeutic doses loperamide is devoid of central effects, it may exert them if used at high doses or combined with drugs that increase its systemic and/or central bioavailability. Recently, public health and scientific interest on loperamide has increased due to a growing trend of misuse and abuse, and consequent reports on its toxicity. Our aim was to evaluate in the rat the effects of increasing loperamide doses, with increasing likelihood to induce central effects, on gastrointestinal motor function (including gastric dysmotility and nausea-like behavior). Methods: Male Wistar rats received an intraperitoneal injection of vehicle or loperamide (0.1, 1, or 10 mg kg). Three sets of experiments were performed to evaluate: (a) central effects (somatic nociceptive thresholds, immobility time, core temperature, spontaneous locomotor activity); (b) general gastrointestinal motility (serial X-rays were taken 0-8 hours after intragastric barium administration and analyzed semiquantitatively, morphometrically, and densitometrically); and (c) bedding intake (a rodent indirect marker of nausea). Animals from sets 1 and 3 were used to evaluate gastric dysmotility ex vivo at 2 and 4 hours after administration, respectively. Key Results: Loperamide significantly induced antinociception, hypothermia, and hypolocomotion (but not catalepsy) at high doses and dose-dependently reduced gastrointestinal motor function, with the intestine exhibiting higher sensitivity than the stomach. Whereas bedding intake occurred early and transiently, gastric dysmotility was much more persistent. Conclusions and inferences: Our results suggest that loperamide-induced nausea and gastric dysmotility might be temporally dissociated., Ministerio de Ciencia e Innovación (SAF2012‐40075‐C02‐01).

The opioid effect of α-casein fragments related to AYFYPEL and YFYPEL, which had previously shown mucin-stimulatory activity in human goblet cells, was investigated. Peptides YFYPEL and YFYPE showed opioid agonistic activity in guinea pig ileum, and in mouse vas deferens but to a lower extent. Peptides were partly hydrolysed during the assay and several of the resulting fragments lost the N-terminal Tyr residue. Docking of peptides YFYPEL (active) and YFYP (inactive) into the active site of the opioid receptor model showed remarkable differences regarding the flexibility at the third intracellular loop of the receptor and the interaction with Pro at the peptide C-terminus that forced residues Arg and Glu from the receptor to move towards the interior of the binding pocket. The study on human cells HT29-MTX has shown that YFYPEL is the minimum fragment able to stimulate MUC5AC expression., This work has received financial support from projects AGL2015-66886-R from the Spanish Ministry of Economy and Competitiveness (MINECO), SAF2012-40075-C02-01 from the Spanish Ministry of Science and Innovation (MICINN), and FP7-SME-2012-315349 (FOFIND) financed by the European Commission (EC). S. F.-T. acknowledges MINECO for his FPI fellowship.

Multitarget cannabinoids could be a promising therapeutic strategic to fight against Alzheimer's disease. In this sense, our group has developed a new family of indazolylketones with multitarget profile including cannabinoids, cholinesterase and BACE-1 activity. A medicinal chemistry program that includes computational design, synthesis and in vitro and cellular evaluation has allowed to us to achieve lead compounds. In this work, the synthesis and evaluation of a new class of indazolylketones have been performed. Pharmacological evaluation includes functional activity for cannabinoid receptors on isolated tissue. In addition, in vitro inhibitory assays in AChE/BuChE enzymes and BACE-1 have been carried out. Furthermore, studies of neuroprotective effects in human neuroblastoma SH-SY5Y cells and studies of the mechanisms of survival/death in lymphoblasts of patients with Alzheimer's disease have been achieved. The results of pharmacological tests have revealed that some of these derivatives (5, 6) behave as CB2 cannabinoid agonists and simultaneously show BuChE and/or BACE-1 inhibition., The authors gratefully acknowledge the financial support of Ministerio Español de Economía y Competitividad (CTQ2015- 66313-R) and would like to thank to Guadalupe Pablo and Carmen Merino for their excellent technical assistant. The work of MLC was supported by the Centre for Biomedical Research on Neurodegenerative Diseases (CIBERNED). GV was supported by a fellowship from SENECYT (Ecuador). Work dedicated in memoriam to Mercedes González Hormaizteguy, a great women scientist and wonderful person

[Background/Aims]: Gastrointestinal adverse effects have a major impact on health and quality of life in analgesics users. Non-invasive methods to study gastrointestinal motility are of high interest. Fluoroscopy has been previously used to study gastrointestinal motility in small experimental animals, but they were generally anesthetized and anesthesia itself may alter motility. In this study, our aim is to determine, in conscious rats, the effect of increasing doses of 2 opioid (morphine and loperamide) and 1 cannabinoid (WIN 55,212-2) agonists on colonic motility using fluoroscopic recordings and spatio-temporal maps., [Methods]: Male Wistar rats received barium sulfate intragastrically, 20–22 hours before fluoroscopy, so that stained fecal pellets could be seen at the time of recording. Animals received an intraperitoneal administration of morphine, loperamide, or WIN 55,212-2 (at 0.1, 1, 5, or 10 mg/kg) or their corresponding vehicles (saline, Cremophor, and Tocrisolve, respectively), 30 minutes before fluoroscopy. Rats were conscious and placed within movement-restrainers for the length of fluoroscopic recordings (120 seconds). Spatio-temporal maps were built, and different parameters were analyzed from the fluoroscopic recordings in a blinded fashion to evaluate colonic propulsion of endogenous fecal pellets., [Results]: The analgesic drugs inhibited propulsion of endogenous fecal pellets in a dose-dependent manner., [Conclusions]: Fluoroscopy allows studying colonic propulsion of endogenous fecal pellets in conscious rats. Our method may be applied to the noninvasive study of the effect of different drug treatments and pathologies., This work was supported by Ministerio de Ciencia e Innovación (SAF2009-12422-C02-01 and SAF2012-40075-C02-01) and Comunidad de Madrid (S-SAL/0261/2006 and S2010/BMD-2308).

Background: The antineoplastic drugs cisplatin and vincristine induce peripheral neuropathies. The sigma-1 receptor (σ1R) is expressed in areas of pain control, and its blockade with the novel selective antagonist MR-309 has shown efficacy in nociceptive and neuropathic pain models. Our goal was to test whether this compound reduces neuropathic signs provoked by these antitumoural drugs. Methods: Rats were treated with cisplatin or vincristine to induce neuropathies. The effects of acute or repeated administration of MR-309 were tested on mechanical and thermal sensitivity, electrophysiological activity of Aδ-primary afferents in the rat skin–saphenous nerve preparation, and gastrointestinal or cardiovascular functions. Results: Rats treated with antitumourals developed tactile allodynia, while those treated with vincristine also developed mechanical hyperalgesia. These in vivo modifications correlated with electrophysiological hyperactivity (increased spontaneous activity and hyperresponsiveness to innocuous and noxious mechanical stimulation). Animals treated with cisplatin showed gastrointestinal impairment and those receiving vincristine showed cardiovascular toxicity. A single dose of MR-309 strongly reduced both nociceptive behaviour and electrophysiological changes. Moreover, its concomitant administration with the antitumourals blocked the development of neuropathic symptoms, thus restoring mechanical sensitivity, improving the impairment of feeding behaviour and gastrointestinal transit in the cisplatin-treated group along with ameliorating the altered vascular reactivity recorded in rats treated with vincristine. Conclusion: σ1R antagonist, MR-309, reduces sensorial and electrophysiological neuropathic signs in rats treated with cisplatin or vincristine and, in addition, reduces gastrointestinal and cardiovascular side effects. Significance: σ1R antagonism could be an interesting and new option to palliate antitumoural neuropathies., To Ivan Álvarez Rodríguez, Carmen Merino and Guadalupe Pablo for their technical support. Ministerio de Ciencia e Innovación-MICINN (SAF2012-40075- C02- 01) and Esteve, Barcelona, Spain, for their financial support.

[Background] Vincristine is a commonly used chemotherapeutic agent. It is associated with undesirable digestive side effects. However, the impact of vincristine on gastrointestinal structure and motility or its long-term effects have not been deeply studied in animal models. This could be useful in order to develop therapeutic or preventive strategies for cancer patients. The aim of this study was to analyze such effects., [Methods] Rats received saline or vincristine (0.1 mg kg-1 , ip) daily for 10 days. Evaluations were performed during treatment and 2-6 weeks after. Somatic mechano-sensitivity was assessed using von Frey hairs. Gastrointestinal motor function was studied by means of radiographic still images and colonic propulsion of fecal pellets using fluoroscopy videos. Histological assessment of the gut morphology and immunohistochemistry for HuC/D and nNOS were performed in whole-mount myenteric plexus preparations., [Key Results] Peripheral sensitivity was increased in animals treated with vincristine and did not subside 2 weeks after treatment finalization. Vincristine treatment inhibited gastrointestinal motility although this was recovered to normal values with time. Damage in the digestive wall after vincristine treatment was greater in the ileum than in the colon. Villi shortening (in ileum) and large inflammatory nodules still remained 2 weeks after treatment finalization. Finally, the proportion of nNOS-immunoreactive neurons was increased with vincristine and continued to be increased 2 weeks after treatment finalization., [Conclusions and Inferences] Vincristine alters gastrointestinal motility, peripheral sensitivity and mucosal architecture. Vincristine-induced neuropathy (somatic and enteric), intestinal mucosa damage and inflammatory infiltrations are relatively long-lasting., L. Blanco has a contract by Consejería de Educación, Juventud y Deporte from Comunidad de Madrid and Fondo Social Europeo (PEJ15/BIO/TL-0580). This work was supported by Ministerio de Ciencia e Innovación (SAF2012-40075-C02-01), and Comunidad de Madrid (S-SAL/0261/2006; S2010/BMD-2308).

[Background]: In different models of paralytic ileus, cannabinoid receptors are overexpressed and endogenous cannabinoids are massively released, contributing to gastrointestinal dysmotility. The antitumoral drug vincristine depresses gastrointestinal motility and a similar mechanism could participate in this effect. Therefore, our aim was to determine, using CB and CB antagonists, whether an increased endocannabinoid tone is involved in vincristine-induced gastrointestinal ileus. [Methods]: First, we confirmed the effects of vincristine on the gut mucosa, by conventional histological techniques, and characterized its effects on motility, by radiographic means. Conscious male Wistar rats received an intraperitoneal injection of vincristine (0.1-0.5 mg/kg), and barium sulfate (2.5 ml; 2 g/ml) was intragastrically administered 0, 24, or 48 h later. Serial X-rays were obtained at different time-points (0-8 h) after contrast. X-rays were used to build motility curves for each gastrointestinal region and determine the size of stomach and caecum. Tissue samples were taken for histology 48 h after saline or vincristine (0.5 mg/kg). Second, AM251 (a CB receptor antagonist) and AM630 (a CB receptor antagonist) were used to determine if CB and/or CB receptors are involved in vincristine-induced gastrointestinal dysmotility. [Key results]: Vincristine induced damage to the mucosa of ileum and colon and reduced gastrointestinal motor function at 0.5 mg/kg. The effect on motor function was particularly evident when the study started 24 h after administration. AM251, but not AM630, significantly prevented vincristine effect, particularly in the small intestine, when administered thrice. AM251 alone did not significantly alter gastrointestinal motility. [Conclusions]: The fact that AM251, but not AM630, is capable of reducing the effect of vincristine suggests that, like in other experimental models of paralytic ileus, an increased cannabinoid tone develops and is at least partially responsible for the alterations induced by the antitumoral drug on gastrointestinal motor function. Thus, CB1 antagonists might be useful to prevent/treat ileus induced by vincristine., This work was supported by Ministerio de Ciencia e Innovación (SAF2009-12422-C02-01, SAF2012-40075-C02-01), Universidad Rey Juan Carlos—Comunidad de Madrid (URJC-CM-2006-BIO-0604) and Comunidad de Madrid (S-SAL/0261/2006; S2010/BMD-2308).

[Background]: The antineoplastic drug 5-fluoruracil (5-FU) is a pirimidine analog, which frequently induces potentially fatal diarrhea and mucositis. Cannabinoids reduce gastrointestinal motility and secretion and might prevent 5-FU-induced gut adverse effects. Here, we asked whether cannabinoids may prevent diarrhea and mucositis induced by 5-FU in the rat. [Methods]: Male Wistar rats received vehicle or the non-selective cannabinoid agonist WIN 55,212-2 (WIN; 0.5 mg kg injection, 1 injection day, 4 consecutive days) by intraperitoneal (ip) route; on the first 2 days, animals received also saline or 5-FU (150 mg kg injection, cumulative dose of 300 mg kg). Gastrointestinal motor function was radiographically studied after barium contrast intragastric administration on experimental days 1 and 4. Structural alterations of the stomach, small intestine and colon were histologically studied on day 4. PAS staining and immunohistochemistry for Ki67, chromogranin A and CD163 were used to detect secretory, proliferating, and endocrine cells, and activated macrophages respectively. [Key Results]: As shown radiographically, 5-FU induced significant gastric emptying delay (on days 1 and 4) and diarrhea (on day 4). WIN did not significantly alter the motility curves obtained for either control or 5-FU-treated animals but tended to reduce the severity of 5-FU-induced diarrhea and increased permanence of barium from day 1 to the beginning of day 4 in 5-FU-treated animals. 5-FU-induced mucositis was severe and not counteracted by WIN. [Conclusions and Inferences]: 5-FU-induced diarrhea, but not mucositis, was partly prevented by WIN at a low dose. Cannabinoids might be useful to prevent chemotherapy-induced diarrhea., This work was supported by Ministerio de Educación y Ciencia (SAF201-40075-C02-01) and Comunidad de Madrid (S2010/BMD-2308).

Three new fentanyl analogs (compounds 3-4-5) have been synthesized and evaluated for antinociceptive properties using the writhing test. The analgesic property of the active compound, N-[1-phenylpyrazol-3-yl]-N-[1- (2-phenethyl)-4-piperidyl)] propenamide (compound 4), was tested using the hot plate test in mice. Its opioid agonistic activity was characterized using three isolated tissues: guinea pig ileum, mouse vas deferens, and rabbit vas deferens. Compound 4 was as effective as fentanyl or morphine and it showed less antinociceptive potency than fentanyl but it was more potent than morphine. The duration of the antinociception was similar to that of fentanyl. This compound inhibited the electrically evoked contractions of myenteric plexus-longitudinal muscle strips of guinea pig ileum and of mouse vas deferens but not those of rabbit vas deferens. These effects could be reversed by A selective antagonists (naloxone and/or CTOP) but not by the y selective antagonist naltrindole, thus indicating that the compound acted as a A opioid agonist. Finally, the binding data confirmed that compound 4 had high affinity and selectivity for the A-receptor, This work was supported by Spanish government grants SAF 97-0044-CO2 and SAF 00-0114-C02, and Laboratorios del Dr. Esteve, S.A.

The synthesis of new fentanyl analogues in which the benzene ring of the propioanilido group has been replaced by phenylpyrazole is described. Antinociceptive activity was evaluated using the writhing and hot plate tests in mice. Two compounds, 3b and 3d, showed interesting analgesic properties, being more potent than morphine and less than fentanyl but with longer duration of action. These compounds inhibited the electrically evoked muscle contraction of guinea pig ileum and mouse vas deferens but not that of rabbit vas deferens and the effects could be reversed by antagonists (naloxone and/or CTOP), thus indicating that the compounds acted as m agonists. Finally, the binding data confirmed that the compounds had high affinity and selectivity for the m receptor., This work was supported by Spanish grants SAF 97- 0044-CO2 and SAF 00-0114-C02. L.F.C. is recipient of a postdoctoral fellowship from the Basque Government. C.C. is grateful to Dr Esteve S.A. for financial support

Based on numerous pharmacological studies that have revealed an interaction between cannabinoid and opioid systems at the molecular, neurochemical, and behavioral levels, a new series of hybrid molecules has been prepared by coupling the molecular features of two wellknown drugs, ie, rimonabant and fentanyl. The new compounds have been tested for their affinity and functionality regarding CB1 and CB2 cannabinoid and μ opioid receptors. In [35S]-GTPγS (guanosine 5'-O-[gamma-thio]triphosphate) binding assays from the post-mortem human frontal cortex, they proved to be CB1 cannabinoid antagonists and μ opioid antagonists. Interestingly, in vivo, the new compounds exhibited a significant dual antagonist action on the endocannabinoid and opioid systems. © 2014 Fernández-Fernández et al.

ABSTRACT: This letter describes the synthesis and in vitro and in vivo evaluation of dual ligands targeting the cannabinoid and peroxisome proliferator-activated receptors (PPAR). These com- pounds were obtained from fusing the pharmacophores of fibrates and the diarylpyrazole rimonabant, a cannabinoid receptor an- tagonist. They are the first examples of dual compounds with nanomolar affinity for both PPARα and cannabinoid receptors. Besides, lead compound 2 proved to be CB1 selective. Unexpect- edly, the phenol intermediates tested were equipotent (compound 1 as compared to 2) or even more potent (compound 3 as compared with 4). This discovery opens the way to design new dual ligands.

A series of new 2-substituted 1,1-dioxo-1,2,6-thiadiazine-5-carboxylate derivatives have been prepared from monosubstituted sulfamides in order to obtain N-substituted 1,1-dioxo-1,2,6-thiadiazine-5-carboxamides as novel cannabinoid derivatives, analogues of Rimonabant (SR141716A). Their potential functional activity on cannabinoid receptors has been evaluated in vitro and in vivo in mice, showing that two compounds (37 and 39) behave as cannabinoid agonists in vitro. Their potency is lower than that of the reference compound, WIN 55,212-2, but their efficacy is similar to that of this cannabinoid agonist, although no in vivo activity is observed. Another derivative (38) behaves as a cannabinoid antagonist both in vitro and in vivo, being its efficacy and potency similar to that of the well-known antagonist SR141716A, This project is supported by the Ministerio de Ciencia y Tecnologia, SPAIN SAF2003-08003-C02 and SAF2006- 13391-C03.

In the present paper, we wish to report the synthesis and antinociceptive activity of a series of new azaalkane bis(2- aminoimidazolinium) compounds from which, N,N0-di(4,5-dihydro-1H-imidazol-2-yl)-3-aza-1,6-hexanediamine 2a has shown the best analgesic properties in vivo in two different assays (i.e., acetic acid-induced writhing test and hot-plate test in mice), as well as oral bioavailability, Financial support was provided by the Spanish DGICYT (Project SAF 97-0044-C02). C.D was a holder of a Marie Curie Research TrainingGrant for which he thanks the European Commission, Directorate General XII (Science, Research and Development).

Derivatives of N-(1-phenethyl-4-piperidyl)propanamides incorporating guanidinium and 2-aminoimidazolinium groups have been prepared by a synthetic approach involving first introduction of a spacer between the piperidine and the functional group by reductive amination of piperidinone. The formation of each of these functional groups was carried out using N-N′ -di(tert-butoxycarbonyl) thiourea and 2-methylthioimidazolinium iodide, respectively. These structures have been designed to incorporate two pharmacologic goals into one entity. Radioligand binding assays ave been used to study their affinity for opioid (μ δ and κ) and I 2 -imidazoline receptors. Two of them, 10 and 16, showed high affinity for μ opioid receptors and functionally they had moderate analgesic properties in the hot plate and writhing tests. The in vitro studies on guinea pig ileum (GPI) indicated that both compounds are μ opioid agonists. In what concerns I2 -imidazoline receptor activity, these derivatives showed low affinity around 6 to 7 times less than idazoxan. Copyright © 2002 Elsevier Science Ltd.