Synthesis and biological evaluation of novel MB327 analogs as resensitizers for desensitized nicotinic acetylcholine receptors after intoxication with nerve agents

Poisoning with organophosphorus compounds, which can lead to a cholinergic crisis due to the inhibition of acetylcholinesterase and the subsequent accumulation of acetylcholine (ACh) in the synaptic cleft, is a serious problem for which treatment options are currently insufficient. Our approach to broadening the therapeutic spectrum is to use agents that interact directly with desensitized nicotinic acetylcholine receptors (nAChRs) in order to induce functional recovery after ACh overstimulation. Although MB327, one of the most prominent compounds investigated in this context, has already shown positive properties in terms of muscle force recovery, this compound is not suitable for use as a therapeutic agent due to its insufficient potency. By means of in silico studies based on our recently presented allosteric binding pocket at the nAChR, i.e. the MB327-PAM-1 binding site, three promising MB327 analogs with a 4-aminopyridinium ion partial structure (PTM0056, PTM0062, and PTM0063) were identified. In this study, we present the synthesis and biological evaluation of a series of new analogs of the aforementioned compounds with a 4-aminopyridinium ion partial structure (PTM0064-PTM0072), as well as hydroxy-substituted analogs of MB327 (PTMD90–0012 and PTMD90–0015) designed to substitute entropically unfavorable water clusters identified during molecular dynamics simulations. The compounds were characterized in terms of their binding affinity towards the aforementioned binding site by applying the UNC0642 MS Binding Assays and in terms of their muscle force reactivation in rat diaphragm myography. More potent compounds were identified compared to MB327, as some of them showed a higher affinity towards MB327-PAM-1 and also a higher recovery of neuromuscular transmission at lower compound concentrations. To improve the treatment of organophosphate poisoning, direct targeting of nAChRs with appropriate compounds is a key step, and this study is an important contribution to this research

Checklists for Applicants submitting dossiers on Cosmetic Ingredients to be evaluated by the SCCS

Checklists for Applicants submitting dossiers on Cosmetic Ingredients to be evaluated by the SCCSThe SCCS adopted these Checklists on 07 March 2017Checklists for Applicants submitting dossiers on Cosmetic Ingredients to be evaluated by the SCCSThe SCCS adopted these Checklists on 07 March 201

A novel binding site in the nicotinic acetylcholine receptor for MB327 can explain its allosteric modulation relevant for organophosphorus-poisoning treatment

Organophosphorus compounds (OPCs) are highly toxic compounds that can block acetylcholine esterase (AChE) and thereby indirectly lead to an overstimulation of muscarinic and nicotinic acetylcholine receptors (nAChRs). The current treatment with atropine and AChE reactivators (oximes) is insufficient to prevent toxic effects, such as respiratory paralysis, after poisonings with various OPCs. Thus, alternative treatment options are required to increase treatment efficacy. Novel therapeutics, such as the bispyridinium non-oxime MB327, have been found to reestablish neuromuscular transmission by interacting directly with nAChR, probably via allosteric mechanisms. To rationally design new, more potent drugs addressing nAChR, knowledge of the binding mode of MB327 is fundamental. However, the binding pocket of MB327 has remained elusive. Here, we identify a new potential allosteric binding pocket (MB327-PAM-1) of MB327 located at the transition of the extracellular to the transmembrane region using blind docking experiments and molecular dynamics simulations. MB327 forms striking interactions with the receptor at this site. The interacting amino acids are highly conserved among different subunits and different species. Correspondingly, MB327 can interact with several nAChR subtypes from different species. We predict by rigidity analysis that MB327 exerts an allosteric effect on the orthosteric binding pocket and the transmembrane domain after binding to MB327-PAM-1. Furthermore, free ligand diffusion MD simulations reveal that MB327 also has an affinity to the orthosteric binding pocket, which agrees with recently published results that related bispyridinium compounds show inhibitory effects via the orthosteric binding site. The newly identified binding site allowed us to predict structural modifications of MB327, resulting in the more potent resensitizers PTM0062 and PTM0063

Opinion of the Scientific Committee on consumer safety (SCCS) - Final opinion on the safety of fragrance ingredient Acetylated Vetiver Oil (AVO) - (Vetiveria zizanioides root extract acetylated) - Submission III

On the basis of the safety assessment carried out using a conservative approach, the SCCS considers the use of Acetylated Vetiver Oil (AVO) with 1% alpha-tocopherol as a fragrance ingredient in cosmetic leave-on and rinse-off type products safe at the concentrations proposed by IFRA. Acetylated Vetiver Oil (AVO) contains some constituents that belong to the chemical group of aldehydes and ketones that are known to be reactive towards biological entities, such as DNA and proteins. However, the overall health risk of such components is likely to be negligible at the concentrations intended to be used in cosmetics products. The SCCS has noted that Acetylated Vetiver Oil (AVO) is a moderate skin sensitiser in test animals. Considering the results of the HRIPT study and the fact that AVO has been used for years in cosmetics without evidence of sensitising potential, it is unlikely that AVO would be causing contact allergy in humans. Inhalation toxicity of Acetylated Vetiver Oil (AVO) was not assessed in this Opinion because no data were provided. Assessment of the inhalation risk would be needed if Acetylated Vetiver Oil (AVO) was intended to be used in sprayable products

Opinion of the Scientific Committee on Consumer safety (SCCS) - Opinion on Ethylzingerone - 'Hydroxyethoxyphenyl Butanone' (HEPB) - Cosmetics Europe No P98-CAS No 569646-79-3-Submission II (eye irritation)

Based on the new information provided by the Applicant, the SCCS considers the use of Hydroxyethoxyphenyl Butanone (HEPB) as a cosmetic preservative in rinse-off, oral care and leave-on cosmetic products with a maximum concentration of 0.7% safe with regard to eye irritation

SCCS addendum to the opinion Climbazole (P64) - SCCS/1506/13

International audienc

The SCCS scientific advice on the safety of nanomaterials in cosmetics

The Cosmetic Regulation (EC) No 1223/2009 specifically covers the risk of nanomaterials used in cosmetic products. If there are concerns regarding the safety of a nanomaterial, the European Commission refers it to the SCCS for a scientific opinion. The Commission mandated the SCCS to identify the scientific basis for safety concerns that could be used as a basis for identifying and prioritising nanomaterials for safety assessment, and to revisit previous inconclusive SCCS opinions on nanomaterials to identify any concerns for potential risks to the consumer health. The SCCS Scientific Advice identified the key general aspects of nanomaterials that should raise a safety concern for a safety assessor/manager, so that the nanomaterial(s) in question could be subjected to safety assessment to establish safety to the consumer. The Advice also developed a list of the nanomaterials notified to the Commission for use in cosmetics in an order of priority for safety assessment, and revisited three previous inconclusive opinions on nanomaterials to highlight concerns over consumer safety that merited further safety assessment

Opinion of the Scientific Committee on Consumer safety (SCCS) – Opinion on Ethylzingerone - ‘Hydroxyethoxyphenyl Butanone’ (HEPB) - Cosmetics Europe No P98 - CAS No 569646-79-3 - Submission II (eye irritation)

International audienc

SCCS OPINION ON Opinion on titanium dioxide (nano form) coated with cetyl phosphate, manganese dioxide or triethoxycaprylylsilane as UV-filter in dermally applied cosmetic" – SCCS 1580/16 – Final version

International audienc