Novel 5-HT7 receptor antagonists modulate intestinal immune responses and reduce severity of colitis.

Inflammatory bowel disease (IBD) encompasses several debilitating chronic gastrointestinal (GI) inflammatory disorders, including Crohn's disease and ulcerative colitis. In both conditions, mucosal inflammation is a key clinical presentation associated with altered serotonin (5-hydroxytryptamine or 5-HT) signaling. This altered 5-HT signaling is also found across various animal models of colitis. Of the 14 known receptor subtypes, 5-HT receptor type 7 (5-HT7) is one of the most recently discovered. We previously reported that blocking 5-HT signaling with either a selective 5-HT7 receptor antagonist (SB-269970) or genetic ablation alleviated intestinal inflammation in murine experimental models of colitis. Here, we developed novel antagonists, namely, MC-170073 and MC-230078, which target 5-HT7 receptors with high selectivity. We also investigated the in vivo efficacy of these antagonists in experimental colitis by using dextran sulfate sodium (DSS) and the transfer of CD4+CD45RBhigh T cells to induce intestinal inflammation. Inhibition of 5-HT7 receptor signaling with the antagonists, MC-170073 and MC-230078, ameliorated intestinal inflammation in both acute and chronic colitis models, which was accompanied by lower histopathological damage and diminished levels of proinflammatory cytokines compared with vehicle-treated controls. Together, the data reveal that the pharmacological inhibition of 5-HT7 receptors by these selective antagonists ameliorates the severity of colitis across various experimental models and may, in the future, serve as a potential treatment option for patients with IBD. In addition, these findings support that 5-HT7 is a viable therapeutic target for IBD.NEW & NOTEWORTHY This study demonstrates that the novel highly selective 5-HT7 receptor antagonists, MC-170073 and MC-230078, significantly alleviated the severity of colitis across models of experimental colitis. These findings suggest that inhibition of 5-HT7 receptor signaling by these new antagonists may serve as an alternative mode of treatment to diminish symptomology in those with inflammatory bowel disease.

Selectivity profile comparison for certain γ-butyrolactone and oxazolidinone-based ligands on a sigma 2 receptor over sigma 1: a molecular docking approach.

Sigma receptors (σ1 R and σ2 R) are pharmacologically characterized membrane-bound receptors that bind a wide range of chemical compounds. Alzheimer's disease, traumatic brain injury, schizophrenia, and neuropathic pain have all been associated with abnormal σ2 activity. The σ2 receptor has recently been identified as a potential therapeutic target for inhibiting the formation of amyloid plaques. Numerous laboratories are now investigating the potential of σ2 ligands. Small molecule discovery is the focus of current research, with the goal of using target-based action to treat a variety of illnesses and ailments. Functionalized γ-butyrolactone and oxazolidinone-based ligands, in particular, are pharmacologically important scaffolds in drug discovery research and have been thoroughly examined for σ2 receptor efficacy. The purpose of this study was to evaluate the pharmacophoric features of different σ2 receptor ligands using in silico techniques. This study used a library of 58 compounds having a γ-butyrolactone and oxazolidinone core. To investigate the binding characteristics of the ligands with the σ2 receptor, a 3D homology model was developed. To understand the binding pattern of the γ-butyrolactone and oxazolidinone based ligands, molecular docking studies were performed on both σ1 and σ2 receptors. Furthermore, MM/GBSA binding energy calculations were used to confirm the binding of ligands on the σ2 over σ1 receptor. These in silico findings will aid in the discovery of selective σ2 ligands with good pharmacophoric properties and potency in the future.

Pharmacology and Therapeutic Potential of the 5-HT7 Receptor.

It is well-documented that serotonin (5-HT) exerts its pharmacological effects through a series of 5-HT receptors. The most recently identified member of this family, 5-HT7, was first identified in 1993. Over the course of the last 25 years, this receptor has been the subject of intense investigation, and it has been demonstrated that 5-HT7 plays an important role in a wide range of pharmacological processes. As a result of these findings, modulation of 5-HT7 activity has been the focus of numerous drug discovery and development programs. This review provides an overview of the roles of 5-HT7 in normal physiology and the therapeutic potential of this interesting drug target.

Ether and Carbamate Derivatives of 3-quinuclidinol and 3- hydroxymethylquinuclidine: Synthesis and Evaluation as Nicotinic Ligands.

BACKGROUND: A lead quinuclidine-based nicotinic ligand (EQA) served as the basis for the design of novel compounds. A new series of 3-substituted quinuclidines was designed, synthesized and evaluated as nicotinic ligands. METHODS: The goal was to improve affinity for nicotinic receptors in the CNS. Interatomic distance calculations were performed on the proposed compounds as well as, known nicotinic ligands. The proposed compounds were then synthesized, characterized and evaluated in in vitro assays as nicotinic receptor ligands. RESULTS: Compounds 9a and 9b were found to inhibit the specific binding of 3H-(S)-Nicotine with Ki values of 48 nM and 42 nM respectively, indicating high affinity interactions with the α4ß2 subtype. Data suggest that several compounds act as partial agonists at CNS receptors with an efficacy between 28 and 40% and are potent partial activators of human muscle type receptors (α1ß1γδ Emax= 80% that of 100 µM nicotine). CONCLUSIONS: Together these results indicate a partial agonism at muscle type receptors (ca. 40%) with no significant activation of rat ganglion-type receptors (α3ß4*: asterisk indicates potential additional subunit that could partner to form the ganglionic receptor). The partial agonism inducing dopamine release from striatal synaptosomes (α4ß2α6α4ß2ß3, and/or α6ß2ß3) suggest that these compounds may in addition be acting at the α4ß2 and/or the α6ß3* receptors. The partial agonists reported herein are interesting nicotinic ligands worthy of further investigation.

Bioisosteric replacement and related analogs in the design, synthesis and evaluation of ligands for muscarinic acetylcholine receptors.

Previous structure-activity relationship studies involving a series of lactone-based muscarinic ligands identified a lead compound containing a diphenylmethylpiperazine moiety (4; IC50 = 340 nM). The purpose of the present work is to investigate 1,3-benzodioxoles, 4,4-diethyl substituted tetrahydrofurans, 5-substituted oxazolidinones and chromones as bioisosteric replacements for the lactone ring in a novel series of muscarinic ligands. The approach provided compounds with improved % inhibition values and identified a non-selective muscarinic ligand with an IC50 value of 280 nM. The structure-activity relationship for this new series will be discussed. Selected compounds were evaluated in preliminary assays for subtype selectivity and were found to be non-selective.

Design and synthesis of 2-aminothiazole based antimicrobials targeting MRSA.

Privileged structure-based libraries have been shown to provide high affinity lead compounds for a variety of important biological targets. The present study describes the synthesis and screening of a 2-aminothiazole based compound library to determine their utility as antimicrobials, focusing on MRSA. Several of the compounds in this series demonstrated improved antimicrobial activity as compared to ceftriaxone (CTX), a ß-lactam antibiotic. The most potent compound (21) had MICs in the range of 2-4 µg/ml across a panel of Staphylococcus aureus strains. In addition, trifluoromethoxy substituted aminothiazoles and aminobenzothiazoles were found to be potent antimicrobials with MICs of 2-16 µg/ml.

In vivo-formed versus preformed metabolite kinetics of trans-resveratrol-3-sulfate and trans-resveratrol-3-glucuronide.

Metabolites in safety testing have gained a lot of attention recently. Regulatory agencies have suggested that the kinetics of preformed and in vivo-formed metabolites are comparable. This subject has been a topic of debate. We have compared the kinetics of in vivo-formed with preformed metabolites. trans-3,5,4'-Trihydroxystilbene [trans-resveratrol (RES)] and its two major metabolites, resveratrol-3-sulfate (R3S) and resveratrol-3-glucuronide (R3G) were used as model substrates. The pharmacokinetics (PK) of R3S and R3G were characterized under two situations. First, the pharmacokinetics of R3S and R3G were characterized (in vivo-formed metabolite) after administration of RES. Then, synthetic R3S and R3G were administered (preformed metabolite) and their pharmacokinetics were characterized. PK models were developed to describe the data. A three-compartment model for RES, a two-compartment model for R3S (preformed), and an enterohepatic cycling model for R3G (preformed) was found to describe the data well. These three models were further combined to build a comprehensive PK model, which was used to perform simulations to predict in vivo-formed metabolite kinetics. Comparisons were made between in vivo-formed and preformed metabolite kinetics. Marked differences were observed in the kinetics of preformed and in vivo-formed metabolites.

Analytical method development for synthesized conjugated metabolites of trans-resveratrol, and application to pharmacokinetic studies.

Trans-3,5,4'-trihydroxystilbene (trans-resveratrol, RES) exhibits very low bioavailability due to extensive conjugative metabolism. Whether RES metabolites exhibit pharmacologic activity is of great interest. The present study aimed at synthesis of monoconjugates of RES - the 3- and 4' monosulfates (R3S and R4'S), and the 3- and 4' monoglucuronides (R3G and R4'G). Synthesis, purification, and yield are described. Synthesized metabolites were utilized to develop a sensitive LC-MS(n) assay for direct quantitation of all analytes. The assay was validated for intra- and inter-day precision and accuracy. Synthesis of RES conjugates and development and validation of a sensitive bioanalytical assay were applied to pharmacokinetic evaluation of RES and its circulating monoconjugates in C57BL mice. The study is a first report of direct quantitation of RES monosulfates and monoglucuronides. These results will aid in characterizing the disposition of RES and its major or active metabolites in vivo.

A versatile and practical microwave-assisted synthesis of sterically hindered N-arylpiperazines.

A wide-ranging and practical synthesis of structurally diverse, sterically hindered N-arylpiperazines from 2,2'-(4-nitrophenylsulfonylazanediyl) bis(ethane-2,1-diyl) bis(4-nitrobenzenesulfonate) and substituted anilines has been achieved using microwave irradiation in acetonitrile followed by deprotection with PhSH.

Identification of a chromone-based retinoid containing a polyolefinic side chain via facile synthetic routes.

Attempts to prepare substituted chromones as novel retinoids revealed that some chromones were unstable under Wadsworth-Horner-Emmons reaction conditions. Hence, Wittig reactions were used to prepare chromone-based compounds as potential retinoids. Firstly, Wittig reagents prepared from 3-bromomethyl-chromen-4-one were reacted with olefinic-aldehydes to provide the target compounds with all-trans side chains in good yield. The approach supplies a useful general route to structurally diverse chromone-based compounds possessing a variety of side chains. Sequential Wittig reactions were used also to prepare a chromone-based retinoid. These novel compounds were evaluated in binding assays and a high affinity RAR ligand was identified. Crystal structures obtained for two key precursors aided the interpretation of binding data.