Rocío Girón

Long-Acting Fentanyl Analogues: Synthesis and Pharmacology of N-(1-Phenylpyrazolyl)-N-(1-phenylalkyl-4-piperidyl)propanamides

The synthesis of new fentanyl analogues in which the benzene ring of the propioanilido group has been replaced by phenylpyrazole is described.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, and, 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 mu agonists. Finally, the binding data confirmed that the compounds had high affinity and selectivity for the mu receptor.

Chromenopyrazoles: Non‐psychoactive and Selective CB1 Cannabinoid Agonists with Peripheral Antinociceptive Properties

The unwanted psychoactive effects of cannabinoid receptor agonists have limited their development as medicines. These CB1‐mediated side effects are due to the fact that CB1 receptors are largely expressed in the central nervous system (CNS). As it is known that CB1 receptors are also located peripherally, there is growing interest in targeting cannabinoid receptors located outside the brain. A library of chromenopyrazoles designed analogously to the classical cannabinoid cannabinol were synthesized, characterized, and tested for cannabinoid activity. Radioligand binding assays were used to determine their affinities at CB1 and CB2 receptors. Structural features required for CB1/CB2 affinity and selectivity were explored by molecular modeling. Some compounds in the chromenopyrazole series were observed to be selective CB1 ligands. These modeling studies suggest that full CB1 selectivity over CB2 can be explained by the presence of a pyrazole ring in the structure. The functional activities of selected chromenopyrazoles were evaluated in isolated tissues. In vivo behavioral tests were then carried out on the most effective CB1 cannabinoid agonist, 13 a. Chromenopyrazole 13 a did not induce modifications in any of the tested parameters on the mouse cannabinoid tetrad, thus discounting CNS‐mediated effects. This lack of agonistic activity in the CNS suggests that this compound does not readily cross the blood–brain barrier. Moreover, 13 a can induce antinociception in a rat peripheral model of orofacial pain. Taking into account the negative results obtained with the hot‐plate test, the antinociception induced by 13 a in the orofacial test could be mediated through peripheral mechanisms.

Synthesis and opioid activity of new fentanyl analogs.

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 micro selective antagonists (naloxone and/or CTOP) but not by the delta selective antagonist naltrindole, thus indicating that the compound acted as a micro opioid agonist. Finally, the binding data confirmed that compound 4 had high affinity and selectivity for the micro-receptor.

Combining rimonabant and fentanyl in a single entity: preparation and pharmacological results

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.

May cannabinoids prevent the development of chemotherapy-induced diarrhea and intestinal mucositis? Experimental study in the rat

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.

New benzimidazole derivatives: selective and orally active 5-HT3 receptor antagonists

The synthesis of new 5-HT(3) receptor antagonists is an interesting field of research because of their wide therapeutic use. The aim of this work is to functionally characterise a new series of benzimidazole derivatives previously described. These compounds bind to 5-HT(3) receptors and have been evaluated using in vitro (rat tunica muscularis mucosae) and in vivo tests (Bezold-Jarisch reflex in rat and gastrointestinal motility and spontaneous motility in mice). Ondansetron and 1-[4-amino-5-chloro-2-(3,5-dimethoxyphenil)methyloxy]-3-[1-[2-methylsulfonylamino]piperidin-4-yl]propan-1-one hydrochloride (RS 39604) were used as well known 5-HT(3) and 5-HT(4) receptor antagonists. These benzimidazole derivatives have proved to be 5-HT(3) receptor antagonists. Interestingly, they are as active as ondansetron when they are intraperitoneally (i.p.) or orally (p.o.) administered and, in mice, they seem to induce fewer behavioural changes at similar effective doses than does ondansetron. The present results confirm the usefulness of the previously proposed pharmacophore and justify the interest in these new benzimidazole derivatives.

Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats

E‐52862 (S1RA, 4‐[2‐[[5‐methyl‐1‐(2‐naphthalenyl)‐1H‐pyrazol‐3‐yl]oxy]ethyl]‐morpholine), a novel selective sigma 1 receptor (σ1R) antagonist, has demonstrated efficacy in nociceptive and neuropathic pain models. Our aim was to test if σ1R blockade with E‐52862 may modify the signs of neuropathy in Zucker diabetic fatty (ZDF) rats, a type 2 diabetes model.

X‐ray analysis of gastrointestinal motility in conscious mice. Effects of morphine and comparison with rats

Non‐invasive methods to study gastrointestinal (GI) motility are of high interest, particularly in chronic studies. Amongst these, radiographic techniques after contrast intragastric administration may offer many advantages. In previous studies, we have successfully and reproducibly applied these techniques together with a semiquantitative analysis method to characterize the effect of different drugs, acutely or repeatedly administered in rat models, but we have never before used these techniques in mice. These are very convenient in basic research. Our aim was to determine if our method is also valid in mice. Additionally, we determined the effect of morphine on GI motor function in both species.

Discovery of Potent Dual PPARα Agonists/CB1 Ligands

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 compounds were obtained from fusing the pharmacophores of fibrates and the diarylpyrazole rimonabant, a cannabinoid receptor antagonist. 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. Unexpectedly, 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.

Involvement of Cannabinoid Signaling in Vincristine-Induced Gastrointestinal Dysmotility In The Rat

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 CB1 and CB2 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 CB1 receptor antagonist) and AM630 (a CB2 receptor antagonist) were used to determine if CB1 and/or CB2 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.