Design, synthesis, and subtype selectivity of 3,6-disubstituted b-carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents for treatment of alcohol abuse

A series of 3,6-disubstituted ß-carbolines was synthesized and evaluated for their in vitro affinities at axß3V2 GABAA/benzodiazepine receptor subtypes by radioligand binding assays in search of a1 subtype selective ligands to treat alcohol abuse. Analogues of ß-carboline-3-carboxylate-t-butyl ester (ßCCt, 1) were synthesized via a CDI-mediated process and the related 6-substituted ß-carboline-3-carboxylates 6 including WYS8 (7) were synthesized via a Sonogashira or Stille coupling processes from 6-iodo-ßCCt (5). The bivalent ligands of ßCCt (32 and 33) were also designed and prepared via a palladium-catalyzed homocoupling process to expand the structure-activity relationships (SAR) to larger ligands

Design, synthesis, and subtype selectivity of 3,6-disubstituted β-carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents for treatment of alcohol abuse

A series of 3,6-disubstituted β-carbolines was synthesized and evaluated for their in vitro affinities at αxβ3γ2 GABAA/benzodiazepine receptor subtypes by radioligand binding assays in search of α1 subtype selective ligands to treat alcohol abuse. Analogues of β-carboline-3-carboxylate-t-butyl ester (βCCt, 1) were synthesized via a CDI-mediated process and the related 6-substituted β-carboline-3-carboxylates 6 including WYS8 (7) were synthesized via a Sonogashira or Stille coupling processes from 6-iodo βCCt (5). The bivalent ligands of βCCt (32 and 33) were also designed and prepared via a palladium-catalyzed homocoupling process to expand the structure-activity relationships (SAR) to larger ligands. Based on the pharmacophore/receptor model, a preliminary SAR study on 34 analogues illustrated that large substituents at position -6 of the β-carbolines were well tolerated. As expected, these groups are proposed to project into the extracellular domain (LDi region) of GABAA/Bz receptors (see 32 and 33). Moreover, substituents located at position -3 of the β-carboline nucleus exhibited a conserved stereo interaction in lipophilic pocket L1, while N(2) presumably underwent a hydrogen bonding interaction with H1. Three novel β-carboline ligands (βCCt, 3PBC and WYS8), which preferentially bound to α1 BzR subtypes permitted a comparison of the pharmacological efficacies with a range of classical BzR antagonists (flumazenil, ZK93426) from several different structural groups and indicated these β-carbolines were “near GABA neutral antagonists”. Based on the SAR, the most potent (in vitro) α1 selective ligand was the 6-substituted acetylenyl βCCt (WYS8, 7). Earlier both βCCt and 3PBC had been shown to reduce alcohol self-administration in alcohol preferring (P) and high alcohol drinking (HAD) rats but had little or no effect on sucrose self-administration.1–3 These data prompted the synthesis of the β-carbolines presented here

A review of non-destructive testing techniques for the in-situ investigation of fretting fatigue cracks

© 2020 The Authors Fretting fatigue can significantly reduce the life of components, leading to unexpected in-service failures. This phenomenon has been studied for over a century, with significant progress being made during the past decade. There are various methods that have been used to study fretting fatigue cracks in order to gain a greater understanding of the effects of fretting fatigue. Destructive methods are traditionally used to observe fretting fatigue cracks. Although useful in determining crack location, crack length, crack propagation modes, crack path and shape, it is not efficient or reliable for time based measurements. Non-destructive testing has developed in recent years and now in-situ monitoring can be used during testing in order to increase the understanding of fretting fatigue. This paper presents a review of non-destructive testing techniques used in-situ during fretting fatigue testing, which are compared in order to conclude the suitability of each technique. Recent developments in non-destructive techniques that could be also applied for fretting fatigue tests are also discussed, as well as recommendations for future research made

A 12-week Double-blind, Comparison of Olanzapine vs Haloperidol in the Treatment of Acute Mania

GesondheidswetenskappePsigiatriePlease help us populate SUNScholar with the post print version of this article. It can be e-mailed to: [email protected]