Tao Xin

6-Bicyclopiperazinyl-1-arylsulfonylindoles and 6-bicyclopiperidinyl-1-arylsulfonylindoles derivatives as novel, potent, and selective 5-HT6 receptor antagonists

A novel series of 6-bicyclopiperazinyl-1-arylsulfonylindoles and 6-bicyclopiperidinyl-1-arylsulfonylindoles derivatives was synthesized and found to be potent and selective 5-HT6 receptor antagonists.

Discovery and characterization of AZD9272 and AZD6538—Two novel mGluR5 negative allosteric modulators selected for clinical development

AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step. Both are highly potent and selective for the human as well as the rat mGluR5 where they interact at the same binding site than MPEP. They are orally available, allow for long interval administration due to a high metabolic stability and long half-lives in rats and permeate the blood brain barrier to a high extent. AZD9272 has progressed into phase I clinical studies.

Recent progress in 5-HT7 receptors: potential treatment of central and peripheral nervous system diseases

In light of the barrage of recent reviews on 5-HT7 receptor agonists and antagonists, this article will highlight and review the research advances published in the patent literature between January 1997 and December 2003. The article is supplemented with selected references on the design, synthesis and development of novel 5-HT7 agents to treat central and peripheral nervous system diseases. Emphasis is placed on recent advances in the possible involvement of 5-HT7 serotonergic agents in the treatment of learning and memory, depression, schizophrenia and migraine. By no means has any attempt been made to exhaustively review the literature, but rather, primary references together with citations to recent literature reviews have been included in each section.

5-Alkyltryptamine derivatives as highly selective and potent 5-HT1D receptor agonists.

A series of 5-alkyltryptamines (6) and the corresponding conformationally constrained analogues (8) have been synthesized. The structure activity relationships (SAR) at the 5-position of the indole skeleton and the ethylamine side chain have been studied. Functional activities were assessed using isolated rabbit saphenous vein. Potent, selective ligands were found (6e, Ki 2.5 nM, 5-HT1B/5-HT1D 125-fold) that have potential for treating acute migraine.

The anti-epileptic drug lacosamide (Vimpat) has anxiolytic property in rodents.

Lacosamide ((R)-2-acetamido-N-benzyl-3-methoxypropionamide; formerly harkoseride, SPM 927; Vimpat), has been recently approved by US and European regulatory authorities for use as add-on therapy for partial-onset seizures in adults. Because a number of anti-epileptic drugs are used to treat conditions beyond epilepsy, including anxiety, in the present study we investigated the anxiolytic potential of lacosamide in a conditioned emotional response (CER) model in rat, and the mouse marble burying assay. In each test lacosamide produced a significant effect consistent with anxiolysis, i.e. lacosamide increased suppression ratio in the CER test, and reduced the number of marbles buried in the marble burying assay. The doses necessary for an anxiolytic effect were higher than those necessary for efficacy in seizure tests conducted in the same species. For example in the mouse, the lacosamide oral ED(50) in the maximal electroshock seizure (MES) and 6 Hz tests was 5.3 and 9.6 mg/kg respectively, and the minimal effective dose in the marble burying assay was 30 mg/kg. In both seizure and anxiety tests, the (S)-enantiomer of lacosamide was inactive suggesting a similar mechanism of action, possibly use-dependent inhibition of sodium channel function (Errington et al., 2008). Efficacy in the CER model was equivalent to diazepam and pregabalin (Lyrica). In tests of side-effects, lacosamide had no effect on choice accuracy in the delayed match to position task of working memory, although at the 30 mg/kg dose, response rates and response latencies were significantly affected. In sum, the present results identify for the first time, an anxiolytic potential of lacosamide.

Synthesis of chiral and geometrically defined 5,5-diaryl-2-amino-4-pentenoates: novel amino acid derivatives

Abstract A novel series of 5,5-diaryl-2-amino-4-pentenoates were synthesized. Chirally defined substrates were obtained efficiently using Oppolzers sultam as a chiral auxiliary and a palladium-catalyzed stereoselective hydrostannylation.

1-(Bicyclopiperazinyl)ethylindoles and 1-(homopiperazinyl)ethyl-indoles as highly selective and potent 5-HT7 receptor ligands

A novel series of 1-(bicyclopiperazinyl)ethylindole and 1-(homopiperazinyl)ethyl-indole derivatives was synthesized and found to be potent and selective 5-HT(7) receptor ligands.