Improved efficacy, tolerance, safety, and abuse liability profile of the combination of CR4056 and morphine over morphine alone in rodent models.

Background And Purpose: Prolonged use of opioids causes analgesic tolerance and adverse effects including constipation and dependence. Compounds targeting imidazoline I receptors are known to potentiate opioid analgesia in rodents. We investigated whether combination with the I receptor ligand CR4056 could improve efficacy and safety of morphine and explored the mechanisms of the CR4056-opioid interaction.

CR4056, a powerful analgesic imidazoline-2 receptor ligand, inhibits the inflammation-induced PKCε phosphorylation and membrane translocation in sensory neurons.

Background And Purpose: CR4056 is a first-in-class imidazoline-2 (I ) receptor ligand characterized by potent analgesic activity in different experimental animal models of pain. In a recent phase II clinical trial, CR4056 effectively reduced pain in patients with knee osteoarthritis. In the present study, we investigated the effects of CR4056 on PKCε translocation in vitro and on PKCε activation in vivo in dorsal root ganglia (DRG) neurons.

Post-thaw Addition of Caffeine and/or Pentoxifylline Affect Differently Motility of Horse and Donkey-Cryopreserved Spermatozoa.

To increase sperm motility, several molecules have been tested in mammals. Methylxanthines have shown effects on sperm motility, capacitation, and on in vitro fertilization processes. The aim of the study was to evaluate if the post-thaw addition of caffeine and/or pentoxifylline changes motility parameters of cryopreserved stallion and donkey spermatozoa.

Development of subnanomolar-affinity serotonin 5-HT receptor ligands based on quinoline structures.

Two small series of quinoline derivatives were designed starting from previously published quinoline derivatives and in order to obtain information about their interaction with the 5-HTR binding site. Initially, the structure of and was modified by replacing their basic moiety with that of partial agonist (ML10302) or with that of reference ligand (RS-67-333). Then, the aromatic moieties of 4-quinolinecarboxylates , , and or 4-quinolinecarboxamides , , and were modified into those of 2-quinolinecarboxamides .

Variables affecting semen quality and its relation to fertility in the dog: A retrospective study.

Although semen analysis is routinely used to evaluate the male reproductive potential in the canine species, only a few authors have attempted to relate semen characteristics to donor traits, such as age or weight, and fertility. This study evaluated the effects of dogs' age (young: 0-24 months, adult: 25-84 months, old: >84 months), size (small: <15 kg, medium: 16-40 kg, large: >40 kg) and reason for semen collection (evaluation, artificial insemination, cryopreservation or research purposes) on the seminal characteristics and related the main seminal characteristics with fresh AI results. Overall, 251 semen examinations were performed from 140 dogs presented between 2000 and 2015 at the University of Pisa Veterinary Teaching Hospital.

Reproductive parameters of donkey jacks undergoing puberty.

In male donkeys, puberty and the related events have been poorly characterized. The aim of this study was to evaluate the age at which male donkeys reach puberty, and characterize age associated changes in testicular size, testicular blood flow, serum testosterone concentration and semen quality. Every two months, starting at 6 months and finishing at 24 months of age, five male donkeys born in May to July were subjected to B-mode ultrasound examination to assess testicular size and scrotum content and blood serum sampling for testosterone concentration.

Multivalent ligands for the serotonin 5-HT receptor.

5-HT receptors are known to form constitutive dimers in membranes. To explore whether multivalency can enhance ligand interactions and/or efficacy in 5-HT receptors, the structure of the partial agonist ML10302 was modified with oligo(ethylene glycol) chains, thus generating, by a gradual approach, short and long tethered bivalent or tetravalent ligands and the corresponding spanner-linked monovalent controls. Both bivalent and tetravalent ligands displayed a 10-20-fold increase in binding affinity compared to appropriate controls, but no multivalent ligand showed greater binding energy than ML10302 itself.

Phenylindenone isomers as divergent modulators of p38α MAP kinase.

Two new fluorophenylindenone derivatives were designed as potential p38α MAPK modulators by preserving the key interactions of the vicinal pyridine/fluorophenyl pharmacophore with the enzyme protein. Interestingly, these two fluorophenylindenone isomers showed divergent activities, with compound 6 behaving as an inhibitor and 5 as a putative activator. These results were rationalized by docking studies and molecular dynamics simulations in terms of stabilization of DFG loop, by compound 5 in a conformation more accessible to phosphorylation.

Biological profile and bioavailability of imidazoline compounds on morphine tolerance modulation.

Tolerance to opioid administration represents a serious medical alert in different chronic conditions. This study compares the effects of the imidazoline compounds 1, 2, and 3 on morphine tolerance in an animal model of inflammatory pain in the rat. 1, 2, and 3 have been selected in that, although bearing a common scaffold, preferentially bind to α2-adrenoceptors, imidazoline I2 receptors, or both systems, respectively.

Induction of ovulation with buserelin in jennies: in search of the minimum effective dose.

The aim of this study was to evaluate the minimum dose of buserelin acetate (buserelin) able to induce ovulation between 24 and 48 h from treatment (positive response) in estrous jennies. Jennies were studied during a total of 172 estrous cycles: ovarian activity was routinely monitored by ultrasound; when the dominant follicle reached a diameter of 33 ± 1 mm, estrous jennies were treated by subcutaneous administration of different doses of buserelin, 3.3mg (N = 11), 1.

Exploring multitarget interactions to reduce opiate withdrawal syndrome and psychiatric comorbidity.

Opioid addiction is often characterized as a chronic relapsing condition due to the severe somatic and behavioral signs, associated with depressive disorders, triggered by opiate withdrawal. Since prolonged abstinence remains a major challenge, our interest has been addressed to such objective. Exploring multitarget interactions, the present investigation suggests that 3 or its (S)-enantiomer and 4, endowed with effective α2C-AR agonism/α2A-AR antagonism/5-HT1A-R agonism, or 7 and 9-11 producing efficacious α2C-AR agonism/α2A-AR antagonism/I2-IBS interaction might represent novel multifunctional tools potentially useful for reducing withdrawal syndrome and associated depression.

Synthesis and structure-activity relationship studies in serotonin 5-HT4 receptor ligands based on a benzo[de][2,6]naphthridine scaffold.

A small series of serotonin 5-HT4 receptor ligands has been designed from flexible 2-methoxyquinoline compounds 7a,b by applying the conformational constraint approach. Ligands 7a,b and the corresponding conformationally constrained analogues 8a-g were synthesized and their interactions with the 5-HT4 receptor were examined by measuring both binding affinity and the ability to promote or inhibit receptor-G protein coupling. Ester derivative 7a and conformationally constrained compound 8b were demonstrated to be the most interesting compounds showing a nanomolar 5-HT4R affinity similar to that shown by reference ligands cisapride (1) and RS-23,597-190 (4).

Fibromyalgia: nosography and therapeutic perspectives.

Fibromyalgia (FM) is an important cause of morbidity and health expenditure. Severe widespread extra-articular chronic pain, along with nonrestorative sleep, dominates the clinical syndrome. The pathogenesis of FM remains unclear.