Papers by Xavier Codony Soler
Frontiers in Pharmacology, 2019
Up to two-thirds of patients affected by spinal cord injury (SCI) develop central neuropathic pai... more Up to two-thirds of patients affected by spinal cord injury (SCI) develop central neuropathic pain (CNP), which has a high impact on their quality of life. Most of the patients are largely refractory to current treatments, and new pharmacological strategies are needed. Recently, it has been shown that the acute administration of the σ1R antagonist MR309 (previously developed as E-52862) at 28 days after spinal cord contusion results in a dose-dependent suppression of both mechanical allodynia and thermal hyperalgesia in wild-type CD-1 Swiss female mice. The present work was addressed to determine whether MR309 might exert preventive effects on CNP development by repeated administration during the first week after SCI in mice. To this end, the MR309 (16 or 32 mg/kg i.p.) modulation on both thermal hyperalgesia and mechanical allodynia development were evaluated weekly up to 28 days post-injury. In addition, changes in pro-inflammatory cytokine (TNF-α, IL-1β) expression and both the expression and activation (phosphorylation) of the N-methyl-Daspartate receptor subunit 2B (NR2B-NMDA) and extracellular signal-regulated kinases (ERK1/2) were analyzed. The repeated treatment of SCI-mice with MR309 resulted in significant pain behavior attenuation beyond the end of the administration period, accompanied by reduced expression of central sensitization-related mechanistic correlates, including extracellular mediators (TNF-α and IL-1β), membrane receptors/channels (NR2B-NMDA) and intracellular signaling cascades (ERK/pERK). These findings suggest that repeated MR309 treatment after SCI may be a suitable pharmacologic strategy to modulate SCI-induced CNP development.
Psychopharmacology, 2011
In rats, 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists improve learning and memory, but t... more In rats, 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists improve learning and memory, but the effects of agonists are poorly defined. This study investigated the effects of 5-HT(6) receptor agonists and antagonists on a rodent model of recognition memory. Selective 5-HT(6) receptor agonists and antagonists were administered either alone, after a scopolamine-induced impairment, or combined with sub-effective doses of the acetylcholinesterase inhibitor, donepezil, or the glutamate NMDA receptor antagonist, memantine, in a novel object discrimination paradigm in adult rats. After a 4-h inter-trial delay to induce natural forgetting, vehicle-treated rats spent an equivalent time exploring novel and familiar objects during the choice trial. The 5-HT(6) receptor agonists, E-6801 (1.25-10 mg/kg i.p.) and EMD-386088 (5-10 mg/kg i.p.), and antagonists, SB-271046 and Ro 04-6790 (5 and 10 mg/kg), along with donepezil (0.1-3 mg/kg) and memantine (5-20 mg/kg) all produced significant and m...
International Review of Neurobiology, 2010
Publisher Summary The 5-HT6 receptor belongs to the G-protein-coupled receptor (GPCR) family. Thi... more Publisher Summary The 5-HT6 receptor belongs to the G-protein-coupled receptor (GPCR) family. This chapter reviews some reported experimental approaches that can be used for a better functional characterization and classification of 5-HT6 receptor ligands. The chapter summarizes the results obtained using some representative 5-HT6 receptor agonists and antagonists. 5-HT6 receptor functionality is being revealed to be much more complex than initially defined. Based on the existing data and depending on the agonist used, different selective receptor active states that activate different cellular pathways may be achieved. Besides Gs-mediated cAMP formation, other messenger systems may be involved. The full characterization of the functional profile of 5-HT6 receptor is still pending, and new players in the signaling cascade of 5-HT6 receptor could take the stage in the near future.
Psychopharmacology, 2004
More than 20 years after the identification of the sigma receptors as a unique binding site in th... more More than 20 years after the identification of the sigma receptors as a unique binding site in the brain and in the peripheral organs, several questions regarding this receptor are still open. Only one of the subtypes of the receptor has been cloned to date, but the endogenous ligand still remains unknown, and the possible association of the receptor with a conventional second messenger system is controversial. From the very beginning, the sigma receptors were associated with various central nervous system disorders such as schizophrenia or movement disorders. Today, after hundreds of papers dealing with the importance of sigma receptors in brain function, it is widely accepted that sigma receptors represent a new and different avenue in the possible pharmacological treatment of several brain-related disorders. In this review, what is known about the biology of the sigma receptor regarding its putative structure and its distribution in the central nervous system is summarized first. The role of sigma receptors regulating cellular functions and other neurotransmitter systems is also addressed, as well as a short overview of the possible endogenous ligands. Finally, although no specific sigma ligand has reached the market, different pharmacological approaches to the alleviation and treatment of several central nervous system disorders and deficits, including schizophrenia, pain, memory deficits, etc., are discussed, with an overview of different compounds and their potential therapeutic use.
Pain, 2010
The involvement of the 5-HT 7 receptor in nociception and pain, particularly chronic pain (i.e., ... more The involvement of the 5-HT 7 receptor in nociception and pain, particularly chronic pain (i.e., neuropathic pain), has been poorly investigated. In the present study, we examined whether the 5-HT 7 receptor participates in some modulatory control of nerve injury-evoked mechanical hypersensitivity and thermal (heat) hyperalgesia in mice. Activation of 5-HT 7 receptors by systemic administration of the selective 5-HT 7 receptor agonist AS-19 (1 and 10 mg/kg) exerted a clear-cut reduction of mechanical and thermal hypersensitivities that were reversed by co-administering the selective 5-HT 7 receptor antagonist SB-258719. Interestingly, blocking of 5-HT 7 receptors with SB-258719 (2.5 and 10 mg/kg) enhanced mechanical (but not thermal) hypersensitivity in nerve-injured mice and induced mechanical hypersensitivity in sham-operated mice. Effectiveness of the treatment with a 5-HT 7 receptor agonist was maintained after repeated systemic administration: no tolerance to the antiallodynic and antihyperalgesic effects was developed following treatment with the selective 5-HT 7 receptor agonist E-57431 (10 mg/ kg) twice daily for 11 days. The 5-HT 7 receptor co-localized with GABAergic cells in the dorsal horn of the spinal cord, suggesting that the activation of spinal inhibitory GABAergic interneurons could contribute to the analgesic effects of 5-HT 7 receptor agonists. In addition, a significant increase of 5-HT 7 receptors was found by immunohistochemistry in the ipsilateral dorsal horn of the spinal cord after nerve injury, suggesting a ''pain"-triggered regulation of receptor expression. These results support the idea that the 5-HT 7 receptor subtype is involved in the control of pain and point to a new potential use of 5-HT 7 receptor agonists for the treatment of neuropathic pain.
Journal of Medicinal Chemistry, 2005
HPLC-Chromatograms HPLC analysis was performed using Waters Alliance 2690 and 2695 (Software Mill... more HPLC-Chromatograms HPLC analysis was performed using Waters Alliance 2690 and 2695 (Software Millenium 3.20) and Agilent 1100 (software Chemstation A.06.03) equipments with Waters Symmetry C8 3.9µm p.s. 150 x 3.9 mm eluted with a mixture of acetonitrile and water containing 10 mM heptanesulphonate and 25 mM K 3 PO 4 at pH 2.5; Waters Xterra MS-C8 5µm p.s. 150 x 3.9 mm or 100 x 3.5 mm eluted with a mixture acetonitrile containing 0.05% TFA and water containing 0.05% TFA; Waters Xterra MS-C8 3.5µm p.s. 100 x 3 mm eluted with a mixture acetonitrile and water containing 10 mM phosphate buffer at pH 7.0 and Waters Xterra RP8 5µm p.s. 150 x 3.9 mm eluted with a mixture acetonitrile and water containing 10 mM ammonium acetate buffer pH 7.0. S3
European Neuropsychopharmacology, 2002
European Journal of Neuroscience, 2003
Sigma (s) sites are a type of nonopiate receptor whose role has been associated with several beha... more Sigma (s) sites are a type of nonopiate receptor whose role has been associated with several behaviours, including anxiety, depression, analgesia, learning processes and psychosis. Although there are several known s receptor types, only the type I receptor (s1) has been cloned. To uncover the in vivo relevance of s-receptors, we have generated knockout mice for s1. Despite the broad expression pattern found for the s1-gene, homozygous mutant mice are viable, fertile and do not display any overt phenotype, compared with their wildtype litter-mates, in mixed genetic backgrounds. However, a signi®cant decrease in the hypermotility response has been measured in knockout mice upon challenge with ()SKF-10 047, in agreement with the involvement of s1-receptors in the induction of psychostimulant actions. The activity of s2-receptors seems to be unaffected in s1-mutant mice. These knockout mice could contribute to better understand the in vivo role of s-receptors.
Drugs of the Future, 1999
Drug Discovery Today, 2006
Although the 5-hydroxytryptamine 6 (5-HT 6) receptor was discovered only recently, its almost exc... more Although the 5-hydroxytryptamine 6 (5-HT 6) receptor was discovered only recently, its almost exclusive distribution in the brain makes it a promising, novel, target for central nervous system (CNS)-mediated diseases such as Alzheimer's disease (cognitive function), schizophrenia, anxiety and obesity. In the past few years a significant research interest has advanced the understanding of the functional roles and the pharmacophore requirements of this receptor. Two 5-HT 6 receptor antagonists have already entered Phase II clinical trials for the enhancement of cognitive function. Since the first discovery of selective ligands for the 5-HT 6 receptor by HTS in 1998, several medicinalchemistry-driven approaches have delivered highly selective lead structures with well-defined functionalities, starting from either the endogenous ligand 5-HT or the chemical structures identified by HTS. The concept of 'scaffold hopping' has been employed to expand the variability of the available chemical scaffolds and to generate patentable ligands. Supported by pharmacophore models, which have been established recently, the binding and functionality (structure-activity relationships) of the lead structures have been optimized further. The 5-hydroxytryptamine 6 (5-HT 6) receptor is one of the most recent additions to the family of mammalian 5-HT receptors. It was identified in the 1990s through molecular biological approaches [1-3] and belongs to a group of 5-HT receptors (5-HT 4 , 5-HT 6 and 5-HT 7) that are coupled positively to adenylate cyclase [4]. More information on the distribution and functional roles of the 5-HT 6 receptor is given in two recent reviews [5,6]. The 5-HT 6 receptor has no known functional splice variants and it appears to be expressed almost exclusively in the central nervous system (CNS), so it is possible that new therapeutic agents targeted towards 5-HT 6 receptors might have relatively few peripheral side-effects. A 5-HT 6 receptor-knockout mouse has been developed [7]. Transgenic mice that are homozygous for a disruption in the endogenous 5-HT 6 receptor gene have a phenotype of increased anxiety behavior that includes diminished investigation of foreign objects and elevation in Reviews KEYNOTE REVIEW JÖ RG HOLENZ Jö rg Holenz (1968) was born in Bergisch-Gladbach, Germany, and studied chemistry at the universities of Cologne and Würzburg (both in Germany). He received his PhD in 1997, researching on the antimalarial potential of a new class of plant alkaloids of natural and semisynthetic origin. In 1998 he joined Grünenthal, Aachen, Germany, as a medicinal chemist, becoming involved in several projects targeting novel analgesic principles. In addition, from 2000 he worked as a project manager (CMC affairs) of one of Grünenthal's clinical drug candidates. In 2003, he joined Laboratorios Dr. Esteve S.A., Barcelona, Spain, as Head of Medicinal Chemistry. His current research interests comprise mainly CNS drugs, such as analgesics, antidepressants and anxiolytics, as well as memory enhancement, schizophrenia, antiobesity and anti-inflammatory drugs. Besides his work, he enjoys playing volleyball, spending time with his friends and traveling.
British Journal of Pharmacology, 2009
1 E-6837 is a novel, selective and high-affinity 5-HT 6 receptor ligand (pK i : 9.13) which in vi... more 1 E-6837 is a novel, selective and high-affinity 5-HT 6 receptor ligand (pK i : 9.13) which in vitro demonstrates partial agonism at a presumably silent rat 5-HT 6 receptor and full agonism at a constitutively active human 5-HT 6 receptor by monitoring the cAMP signaling pathway. 2 The effects of chronic treatment with E-6837 were determined in diet-induced obese (DIO)-rats on changes in body weight, food and water intake, plasma indices of comorbid risk factors, and weight regain on compound withdrawal. The centrally acting antiobesity drug, sibutramine, was used as the reference comparator. 3 Sustained body weight loss and decreased cumulative food intake of DIO-rats was observed with E-6837 (30 mg kg À1 , p.o., twice a day) during the 4-week treatment period. The onset of the E-6837 effect on body weight was slower than that of sibutramine (5 mg kg À1 , p.o.), while its maximal effect was greater, that is À15.7 versus À11.0%. 4 E-6837-induced weight loss was exclusively mediated by a decrease (31.7%) in fat mass, with a concomitant reduction (49.6%) in plasma leptin. Reduced obesity was also reflected in improved glycemic control. 5 Although weight regain occurred after withdrawal from either compound, the body weights after E-6837 (À6.6%) remained lower than after sibutramine (À3.8%) indicating that the greater efficacy of the former did not result in profound rebound hyperphagia/weight gain. 6 These results show that the 5-HT 6 receptor partial agonist, E-6837, is a promising new approach to the management of obesity with the potential to produce greater sustained weight loss than sibutramine.
British Journal of Pharmacology, 2006
Bioorganic & Medicinal Chemistry Letters, 2007
Based on a pharmacophore alignment on a 5-HT 6 ligand applying 4SCan Ò technology, a new lead ser... more Based on a pharmacophore alignment on a 5-HT 6 ligand applying 4SCan Ò technology, a new lead series was identified and further structurally investigated. K i s down to 8 nM were achieved.
European Journal of Pharmacology, 2013
While opioids are potent analgesics widely used in the management of pain, a number of well-known... more While opioids are potent analgesics widely used in the management of pain, a number of well-known adverse effects limit their use. The sigma-1 receptor is a ligand-regulated molecular chaperone involved in pain processing, including modulation of opioid antinociception. However, data supporting the potential use of sigma-1 receptor ligands as suitable opioid adjuvants are based on studies that use non selective ligands. Also, safety issues derived from combination therapy are poorly addressed. In this study we used the new selective sigma-1 receptor antagonist S1RA (E-52862) to characterize the effect of selective sigma-1 receptor blockade on opioid-induced efficacy-and safety-related outcomes in mice. S1RA (40 mg/kg) had no effect in the tail-flick test but did enhance the antinociceptive potency of several opioids by a factor between 2 and 3.3. The potentiating effect of S1RA on morphine antinociception did not occur in sigma-1 receptor knockout mice, which supports the selective involvement of the sigma-1 receptor. Interestingly, S1RA co-administration restored morphine antinociception in tolerant mice and reverted the reward effects of morphine in the conditioned place preference paradigm. In addition, enhancement of antinociception was not accompanied by potentiation of other opioid-induced effects, such as the development of morphine analgesic tolerance, physical dependence, inhibition of gastrointestinal transit, or mydriasis. The use of sigma-1 receptor antagonists as opioid adjuvants could represent a promising pharmacological strategy to enhance opioid potency and, most importantly, to increase the safety margin of opioids. S1RA is currently in phase II clinical trials for the treatment of several pain conditions.
4-indolilsulfonamidas derivatives, their preparation and their use as medicaments. The present in... more 4-indolilsulfonamidas derivatives, their preparation and their use as medicaments. The present invention relates to new sulfonamide derivatives, of general formula (Ia, Ib). Optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or corresponding solvates , to processes for their preparation, to their application as medicaments in human and / or veterinary and pharmaceutical compositions containing them.
Combinacion de sustancias activas conteniendo al menos un compuesto con afinidad por el receptor ... more Combinacion de sustancias activas conteniendo al menos un compuesto con afinidad por el receptor del neuropeptido Y (NPY) y al menos un compuesto con afinidad por el receptor 5-HT_{6}. La presente invencion se refiere a una combinacion de sustancias activas que comprende al menos un compuesto con afinidad por el receptor del neuropeptido Y y al menos un compuesto con afinidad por el receptor 5-HT_{6}, un medicamento que comprende dicha combinacion de sustancias activas y el uso de dicha combinacion de sustancias activas para la fabricacion de un medicamento.
Utilisation d'un ligand sigma, de preference un ligand sigma de formule (I), pour la preventi... more Utilisation d'un ligand sigma, de preference un ligand sigma de formule (I), pour la prevention ou le traitement de vomissements induits par un agent chimio-therapeutique ou par la radioactivite, en particulier des vomissements induits par des taxanes, des vinca-alcaloides ou des medicaments chimio-therapeutiques renfermant du platine.
7-indolilsulfonamidas derivatives, their preparation and their use as medicaments. The present in... more 7-indolilsulfonamidas derivatives, their preparation and their use as medicaments. The present invention relates to new sulfonamide derivatives, of general formulas (Ia, Ib) optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or salts, corresponding physiologically acceptable solvates preferably salts, or, to processes for their preparation, to their application as medicaments in human and / or veterinary and pharmaceutical compositions containing them .
A medicament comprising an active substance combination comprising at least one compound (A), whe... more A medicament comprising an active substance combination comprising at least one compound (A), wherein said compound (A) is N- [3- (2-dimethylamino-ethyl) -1H-indol-5-yl] - 6-chloroimidazo [2,1-b] thiazole 5-sulfonamide 5 and at least one compound (B), wherein at least one compound (B) is SB-271046, and wherein the medicament optionally also comprises at least a pharmaceutical adjuvant.
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Papers by Xavier Codony Soler