Alma Viso

Arylpiperazine Derivatives Acting at 5-HT1A Receptors

Serotonin (5-hydroxytryptamine, 5-HT) is one of the most attractive targets for medicinal chemists. Among 5-HTRs, the 5-HT(1A) subtype is the best studied and it is generally accepted that it is involved in psychiatric disorders such as anxiety and depression. Several structurally different compounds are known to bind 5-HT(1A)R sites. Among these, arylpiperazine derivatives represent one of the most important classes of 5-HT(1A)R ligands. This article will review the development of arylpiperazine derivatives acting at 5-HT(1A)Rs with an emphasis on structure-affinity relationships of agonists and antagonists, ligand-receptor interactions and pharmacological applications.

Activation of the endocannabinoid system as therapeutic approach in a murine model of multiple sclerosis

Theilers murine encephalomyelitis virus‐induced demyelinating disease (TMEV‐IDD) is a well‐characterized murine model of human multiple sclerosis (MS) that closely resembles the chronic and progressive clinical form of the disease. Recent studies have described the involvement of the cannabinoid system in the progression of the disease and the benefits associated with the administration of cannabinoid agonists. With the objective to study whether “indirect” agonists, that is, compounds able to reinforce the physiological endocannabinoid transmission and, therefore, devoid of the psychotropic effects of “direct” agonists, could be suitable agents for the amelioration of MS neurological deficits, we administered the potent and selective anandamide uptake inhibitor UCM707 to TMEV‐infected mice. Our results indicate that treatment during established disease significantly improves the motor function of the diseased mice. At the histological level, UCM707 is able to reduce microglial activation, diminish major histocompatibility complex class II antigen expression, and decrease cellular infiltrates in the spinal cord. Additionally, in microglial cells, UCM707 decreases the production of the proinflammatory cytokines tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, and IL‐6; reduces nitric oxide levels and inducible nitric oxide synthase expression; and is able to potentiate the action of a subeffective dose of the endocannabinoid anandamide. Overall, these results suggest that agents able to activate the endocannabinoid system could constitute a new series of drugs for the treatment of MS.

UCM707, a potent and selective inhibitor of endocannabinoid uptake, potentiates hypokinetic and antinociceptive effects of anandamide.

To date, UCM707, N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide, has the highest potency and selectivity in vitro as inhibitor of the endocannabinoid transporter, which might make this compound useful in potentiating endocannabinoid transmission, with minimal side-effects, in the treatment of several disorders. However, there is no information about how UCM707 behaves in vivo as regards certain classic effects of endocannabinoids, such as hypomotility and antinociception. In the present work, we tested in rats the dose-response effects of UCM707 in the open-field and hot-plate tests, and, in particular, we analyzed whether this compound enhanced the hypokinetic and/or the antinociceptive actions of anandamide at a subeffective dose, using these two in vivo assays. UCM707, administered alone, had no effect on ambulatory, exploratory and stereotypic activities, time spent in inactivity and sensitivity to noxious heat, with only some small responses at the highest dose used. UCM707, administered at a dose that did not produce any effects by itself or these were very small, was, however, able to significantly potentiate the action of a dose of anandamide that did not produce any effects when it was administered alone. So, the combination of both compounds produced greater decreases in exploratory activity and, particularly in ambulation, increased the time spent in inactivity and the latency to respond to a painful stimulus. In summary, UCM707, as suggested by its in vitro properties, seems also to behave in vivo as a selective and potent inhibitor of the endocannabinoid transporter, showing negligible direct effects on the receptors for endocannabinoids but potentiating the action of these endogenous compounds. This compound is, thus, a promising tool, used alone or in combination with endocannabinoids, for the treatment of a variety of disorders.

Update 1 of: α,β-Diamino Acids: Biological Significance and Synthetic Approaches

The discovery of nonproteinogenic amino acids among natural products, either in native state or as fragments of complex molecules, has increased the level of interest in this family of molecules from different scientific standpoints. Compounds with valuable biological properties can be found among these atypical amino acids. In addition, they have served as building blocks for the synthesis of new molecules or as surrogates of native amino acids in known peptidic entities to modulate their biological behavior. In this context, R, -diamino acids and their derivatives esters and amides, have attracted a great deal of attention among organic chemists and biochemists through the years. This interest has been due to the ubiquitous nature of R, -diamino acids as key structural fragments of biologically active compounds. Beyond this focus, the simplest compound, 2,3-diaminopropionic acid, has recently found application in the environmentally safe production of hydrogen for fuel cells, as a selective carrier of CO2 through gel membranes.1a Also, it has served to assemble a molecular device that produces propelling motion upon IR irradiation1b and, lately, in the context of food chemistry, 2,3-diaminopropionic acid has been identified as an inhibitor of polyphenol oxidase, the enzyme responsible for the browning of fruits and vegetables1c and as an enhancer of Maillard browning.1d In spite of the incidence of these molecules in an increasing number of areas, this review will deal with the biological significance, the therapeutic uses, and other interesting applications of R, -diamino acids and their derivatives found in the existing literature. Additionally, aside from the above considerations, the structural complexity of these molecules, having two vicinal chiral centers has also represented a challenge for synthetic organic chemists, especially the synthesis of enantiopure materials. Therefore, the aim of this article will also be to provide a deep and general view of the existing methodology for the synthesis of aliphatic R, or 2,3-diamino acids and their simple derivatives, esters, * To whom correspondence should be addressed. E-mail: iqov379@ iqog.csic.es. Alma Viso was born in Madrid (Spain) in 1964. She obtained a B.S. degree in Chemistry in 1987 and a Ph.D. in 1992 from Universidad Complutense de Madrid (UCM). In 1992, she moved to Massachusetts Institute of Technology (MIT) as a Fulbright fellow to work with Stephen L. Buchwald for 18 months. She joined the faculty at UCM (Madrid) in 1993 as an Assistant Professor and was promoted to Associate Professor in May 2002. In December 2002, she joined Instituto de Quı́mica Orgánica General, CSIC, as a Staff Researcher (Cientı́fico Titular) and was promoted to Senior Staff Researcher (Investigador Cientı́fico) in 2007. Her current research interests are focused in two main areas, the development of new methodologies in asymmetric synthesis using sulfoxides and sulfinamides and the application of these novel methods to efficient syntheses of therapeutically valuable products. Chem. Rev. PR1

Benzimidazole derivatives. Part 1: Synthesis and structure–activity relationships of new benzimidazole-4-carboxamides and carboxylates as potent and selective 5-HT4 receptor antagonists

New benzimidazole-4-carboxamides 1-16 and -carboxylates 17-26 were synthesized and evaluated for binding affinity at serotonergic 5-HT4 and 5-HT3 receptors in the CNS. Most of the synthesized compounds exhibited moderate-to-very high affinity (in many cases subnanomolar) for the 5-HT4 binding site and no significant affinity for the 5-HT3 receptor. SAR observations and structural analyses (molecular modeling, INSIGHT II) indicated that the presence of a voluminous substituent in the basic nitrogen atom of the amino moiety and a distance of ca. 8.0 A from this nitrogen to the aromatic ring are of great importance for high affinity and selectivity for 5-HT4 receptors. These results confirm our recently proposed model for recognition by the 5-HT4 binding site. Amides 12-15 and esters 24 and 25 bound at central 5-HT4 sites with very high affinity (Ki = 0.11-2.9 nM) and excellent selectivity over serotonin 5-HT3, 5-HT2A, and 5-HT1A receptors (Ki > 1000-10,000 nM). Analogues 12 (Ki(5-HT4) = 0.32 nM), 13 (Ki(5-HT4) = 0.11 nM), 14 (Ki(5-HT4) = 0.29 nM) and 15 (Ki(5-HT4) = 0.54 nM) were pharmacologically characterized as selective 5-HT4 antagonists in the isolated guinea pig ileum (pA2 = 7.6, 7.9, 8.2 and 7.9, respectively), with a potency comparable to the 5-HT4 receptor antagonist RS 39604 (pA2 = 8.2). The benzimidazole-4-carboxylic acid derivatives described in this paper represent a novel class of potent and selective 5-HT4 receptor antagonists. In particular, compounds 12-15 could be interesting pharmacological tools for the understanding of the role of 5-HT4 receptors.

Design, synthesis and biological evaluation of new endocannabinoid transporter inhibitors

In the present work we describe the synthesis and the in vitro evaluation of a series of arachidonic acid derivatives of general structure I as endocannabinoid transporter inhibitors. In addition, we report the first in vivo studies of the most potent derivative (4, UCM707) within this series. The majority of compounds studied are highly potent (IC(50)=24-0.8 micro M) and selective endocannabinoid uptake inhibitors with very low affinities for either the enzyme fatty acid amide hydrolase (IC(50)=30-113 micro M) or for cannabinoid receptor subtype 1 (CB(1)), cannabinoid receptor subtype 2 (CB(2)) and vanilloid receptor subtype 1 (VR(1)) (K(i)=1000-10000 nM). Among them, (5Z,8Z,11Z,14Z)-N-(fur-3-ylmethyl)icosa-5,8,11,14-tetraenamide (UCM707) behaves as the most potent endocannabinoid transporter inhibitor described to date (IC(50)=0.8 micro M) and exhibits improved potency for the anandamide transporter, high selectivity for CB(1) and VR(1) receptors, and modest selectivity for CB(2). In vivo it enhances the analgesia and hypokinetic effects induced by a subeffective dose of anandamide.

Characterization of an anandamide degradation system in prostate epithelial PC-3 cells: synthesis of new transporter inhibitors as tools for this study

The response of anandamide is terminated by a carrier‐mediated transport followed by degradation catalyzed by the cloned enzyme fatty acid amidohydrolase (FAAH). In this study, we provide biochemical data showing an anandamide uptake process and the expression of FAAH in human prostate. Anandamide was accumulated in PC‐3 cells by a saturable and temperature‐dependent process. Kinetic studies of anandamide uptake, determined in the presence of cannabinoid and vanilloid antagonists, revealed apparent parameters of KM=4.7±0.2 μM and Vmax=3.3±0.3 pmol min−1 (106 cells)−1. The accumulation of anandamide was moderately inhibited by previously characterized anandamide transporter inhibitors (AM404, UCM707 and VDM11) but was unaffected by inhibitors of other lipid transport systems (phloretin or verapamil) and moderately affected by the FAAH inhibitor methyl arachidonyl fluorophosphonate. The presence of FAAH in human prostate epithelial PC‐3 cells was confirmed by analyzing its expression by Western blot and measuring FAAH activity. To further study the structural requirements of the putative carrier, we synthesized a series of structurally different compounds 1–8 and evaluated their capacity as uptake inhibitors. They showed different inhibitory capacity in PC‐3 cells, with (9Z,12Z)‐N‐(fur‐3‐ylmethyl)octadeca‐9,12‐dienamide (4, UCM119) being the most efficacious, with maximal inhibition and IC50 values of 49% and 11.3±0.5 μM, respectively. In conclusion, PC‐3 cells possess a complete inactivation system for anandamide formed by an uptake process and the enzyme FAAH. These results suggest a possible physiological function of anandamide in the prostate, reinforcing the role of endocannabinoid system as a neuroendocrine modulator.

3-D-QSAR/CoMFA and recognition models of benzimidazole derivatives at the 5-HT4 receptor

3-D-QSAR/CoMFA methodology and computational simulation of ligand recognition have been successfully applied to explain the binding affinities of a series of benzimidazole derivatives 1-24 acting at serotonin 5-HT(4)Rs. Both derived computational models have facilitated the identification of the structural elements of the ligands that are key to high 5-HT(4)R affinity. The results provide the tools for predicting the affinity of related compounds, and for guiding the design and synthesis of new ligands with predetermined affinities and selectivity.

Design and synthesis of S-(−)-2-[[4-(napht-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine (CSP-2503) using computational simulation. A 5-HT1A receptor agonist

Based on a computational model for 5-HT(1A)R-ligand interaction and QSAR studies, we have designed and synthesized a new series of arylpiperazines 2-8 which exhibit high 5-HT(1A)R affinity and selectivity over alpha(1)-adrenergic receptors. Among them, compound CSP-2503 (4) has been pharmacologically characterized as a 5-HT(1A)R agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties.

The Medicinal Chemistry of Agents Targeting Monoacylglycerol Lipase

Monoacylglycerol lipase (MAGL) has been recently proposed as the main enzymatic activity responsible for the in vivo hydrolysis of the most abundant endocannabinoid in the brain, the 2-arachidonoylglycerol (2-AG). The endocannabinoids, mainly anandamide (AEA) and 2-AG, are a class of lipid messengers that modulate a broad number of physiological processes both in the central nervous system and in the periphery. To date, AEA has been by far the most studied endocannabinoid, although increasing evidence is pointing out the prominent, and sometimes underestimated, role of 2-AG in the regulation of different functions. Therefore, it is of outmost importance to dissect the specific cellular pathways in which these two endocannabinoids are involved. Nonetheless, little is known about the structural require-ments of MAGL. Here we review the current knowledge on MAGL, with special focus on its structure and catalytic mechanism as the rational basis for the design of potent and selective compounds able to interact with it; the inhibitors that have been described to date, and the therapeutic applications that make MAGL an attractive therapeutic target.