Effect of Bulky N-Dibenzofuranylmethyl Substitution on the 5-HT2 Receptor Affinity and Efficacy of a Psychedelic Phenethylamine.

The introduction of arylmethyl substituents on the amine nitrogen atom of phenethylamines and tryptamines often results in profound increases in their affinity and functional activity at 5-HT2 serotonin receptors. To probe the sensitivity of this effect to substantially larger N-substituents, ten derivatives of the well-characterized psychedelic phenethylamine 2C-B were prepared by appending different dibenzo[b,d]furylmethyl (DBFM) moieties to the basic nitrogen. The DBFM group attached to the amino group through its 1-, -2-, or 3-position decreased affinity and agonist activity at the 5-HT2A/2C receptors. Substitution through the 4-position usually favored affinity for all three 5-HT2 receptor subtypes with compound 5 exhibiting 10- and 40-fold higher affinities at the 5-HT2A and 5-HT2C receptors, respectively, but less than fourfold selectivity among the three receptor subtypes. Nevertheless, all were relatively weak partial 5-HT2AR agonists, mostly in the low micromolar range, but full or nearly full agonists at the 5-HT2C subtype as determined in a calcium mobilization assay. Molecular docking simulations suggested that the dibenzofuryl portion dives more deeply into the orthosteric binding site of the 5-HT2A than the 5-HT2C receptor, interacting with the Trp3366.48 toggle switch associated with its activation, while the phenylamine moiety lies close to the extracellular side of the receptor. In conclusion, a very bulky N-substituent on a phenethylamine 5-HT2 receptor agonist is tolerated and may increase affinity if its orientation is appropriate. However, the Gq protein-mediated potencies are generally low, with low efficacy (relative to 5-HT) at the 5-HT2A receptor, somewhat higher efficacy at the 5-HT2B subtype, and full or nearly full efficacy at the 5-HT2C subtype.

Molecular dynamics simulations of the SARS-CoV-2 Spike protein and variants of concern: structural evidence for convergent adaptive evolution.

The Spike protein's structure of the SARS-CoV-2 provides a unique opportunity to consider perturbations at the atomic level. We used the cryo-electron microscopy structure of the open conformation of the Spike protein to assess the impact of the mutations observed in the variants of concern at the molecular level. Molecular dynamics were subsequently performed with both the wt and the mutated forms to compare the flexibility and variation data for each residue of the three-dimensional fluctuations in the region associated with each alpha carbon. Additionally, protein-protein docking was used to investigate the interaction of each mutated profile with the ACE-2 receptor. After the molecular dynamics, the results show that the mutations increased the stability of the trimeric protein, with greater stability observed in the Gamma variant harboring the 10 characteristic mutations. The results of molecular dynamics, as shown by RMSF demonstrated for the residues that comprise the binding domain receptor (RBD), exhibited a reduction in flexibility, which was more pronounced in the Gamma variant. Finally, protein-protein docking experiments revealed an increase in the number of hydrophobic interactions and hydrogen bonds in the Gamma variant against the ACE-2 receptor, as opposed to the other variants. Taken together, these in silico experiments suggest that the evolution of the mutations favored the increased stability of Spike protein while potentially improving its interaction with the ACE-2 receptor, which in turn may indicate putative structural outcomes of the selection of these mutations in the convergent adaptive evolution as it has been observed for SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

O renascimento dos psicodélicos como potenciais agentes psicoterapêuticos: trajetória, avanços recentes e perspectivas / The renaissance of psychedelics as potential psychotherapeutic agents: trajectory, recent advances and perspectives

Utilizados em vários contextos pela humanidade desde tempos imemoriais até os dias atuais, os psicodélicos despertaram a atenção dos pesquisadores na primeira metade do século passado. Desde então, mesmo com o longo período de restrições às pesquisas científicas devido à implementação da Controlled Substance Act em 1970, inúmeras investigações, principalmente nos últimos anos, vêm indicando o renascimento dos psicodélicos como importantes ferramentas em psicoterapia assistida. Esta revisão narrativa pretende divulgar a trajetória de pesquisa de psicodélicos selecionados (LSD, psilocibina, ayahuasca e MDMA), lançando luz sobre estudos clínicos que indicam a eficácia e a segurança médica dessas substâncias no tratamento de distúrbios mentais como depressão, ansiedade, dependência química e transtorno de estresse pós-traumático. Adicionalmente, também são apontados alguns eventos históricos e culturais relevantes que, de alguma forma, dialogam com esta trajetória.(AU)

Used in various contexts by mankind from immemorial time to nowadays, psychedelics aroused the attention of researchers in the first half of last century. Since then, even with the long period of restrictions on scientific research due to the implementation of the Controlled Substance Act in 1970, accumulated investigations, especially in recent years, have been indicating the renaissance of psychedelics as important tools in assisted psychotherapy. This narrative review intends to disclose the research trajectory of selected psychedelics (LSD, psilocybin, ayahuasca and MDMA) shedding light on clinical studies which support medical efficacy and safety of these substances to treat mental diseases such as depression, anxiety, substance use disorder and post-traumatic stress disorder. Additionally, some relevant historical and cultural events that somehow had dialogued with this trajectory are also approached.(AU)

Utilizados en diversos contextos por la humanidad desde tiempos inmemoriales hasta nuestros días, los psicodélicos despertaron la atención de los investigadores en la primera mitad del siglo pasado. Desde entonces, incluso con el largo período de restricciones en las investigaciones científicas debido a la implementación de la Controlled Substance Act en 1970, numerosas investigaciones, principalmente en los últimos años, han indicado el resurgimiento de los psicodélicos como herramientas importantes en la psicoterapia asistida. Esta revisión narrativa tiene como objetivo dar a conocer la trayectoria de investigación de psicodélicos seleccionados (LSD, psilocibina, ayahuasca y MDMA), arrojando luz sobre estudios clínicos que demuestran la eficacia médica y la seguridad de estas sustancias en el tratamiento de desordenes mentales como la depresión, la ansiedad, dependencia química y trastorno de estrés postraumático. Adicionalmente, también se señalan algunos hechos históricos y culturales relevantes que, de alguna manera, dialogan con esta trayectoria.(AU)

Resultados iniciais e tardios de diabéticos tratados com stents farmacológicos do Registro Safira / Early and late outcomes of diabetic patients treated with drug-eluting stents in the Safira Registry

INTRODUÇÃO: O tratamento percutâneo da doença arterial coronária foi revolucionado pelo uso dos stents farmacológicos (SF). No entanto, sua utilização na prática diária envolve pacientes com características clínicas e angiográficas mais complexas dos que aquelas encontradas em estudos randomizados. Este registro se propôs a caracterizar, em nosso meio, diabéticos e seus desfechos clínicos após implante de SF. MÉTODOS: Registro unicêntrico, prospectivo, que arrolou pacientes consecutivos submetidos a implante de SF. Foram registrados dados clínicos, angiográficos e do procedimento, assim como os desfechos hospitalares e tardios. A avaliação do desfecho primário, composto por óbito cardíaco, infarto agudo do miocárdio ou revascularização da lesão-alvo, foi realizada comparando-se pacientes diabéticos e não diabéticos. RESULTADOS: Avaliamos 1.670 pacientes tratados com SF no período de 2002 a 2012, com seguimento de 3,2 ± 2,5 anos. Um terço dos pacientes era diabético e apresentou sobrevivência livre de eventos menor que os não diabéticos (79,4% vs. 82,6%; P = 0,02). A razão de risco ajustada, no entanto, foi de 1,22 (IC 95%, 0,89-1,69) - não significativa. Ao analisar o subgrupo dos pacientes em uso de insulina, encontramos sobrevivência livre de eventos significativamente menor que a dos demais, enquanto que os diabéticos que não estavam em uso de insulina mostraram comportamento semelhante ao dos não diabéticos (68,7% vs. 83,9% vs. 82,8%, respectivamente; P < 0,01). A razão de risco ajustada foi 1,72 (IC 95%, 1,13-2,63) vez maior para os diabéticos em uso de insulina em comparação aos demais pacientes. CONCLUSÕES: O uso de SF traz benefícios para todos os diabéticos, especialmente para os que não utilizam insulina.

BACKGROUND: The percutaneous treatment of coronary artery disease has been revolutionized by the use of drug-eluting stents (DES). However, its use in the daily practice involves patients with more complex clinical and angiographic characteristics than those found in randomized trials. This registry was designed to characterize diabetic patients and their outcomes following DES implantation in our country. METHODS: Prospective single-center registry enrolling consecutive patients after DES implantation. Clinical, angiographic and procedure-related data, as well as early and long-term outcomes were recorded. The primary endpoint, including cardiac death, myocardial infarction or target lesion revascularization, was compared between diabetics and non-diabetics. RESULTS: We evaluated 1,670 patients treated with DES from 2002 to 2012 with a follow-up of 3.2 ± 2.5 years. One third of the patients were diabetic and had lower event-free survival when compared to non-diabetic patients (79.4% vs. 82.6%; P = 0.015). The adjusted odds ratio, however, was 1.22 (95% CI, 0.89-1.69) and was not significant. A significantly lower event-free survival was observed in the subgroup of patients receiving insulin, whereas it was similar for diabetic and non-diabetic patients in the subgroup not receiving insulin (68.7% vs. 83.9% vs. 82.8%, respectively; P < 0.01). The adjusted odds ratio was 1.72 (95% CI, 1.13-2.63) higher for diabetic patients receiving insulin when compared to the remaining patients. CONCLUSIONS: The use of DES is beneficial for all diabetic patients, especially those who do not receive insulin.

Oral administration of piperine for the control of aflatoxin intoxication in rats

Aflatoxins are mycotoxins that have important toxic effects on human and animal health, even if consumed at low doses. The oral administration of piperine (1.12 mg/kg) during 23 days in rats seemingly interfered with the toxicity of aflatoxins, decreasing hepatic injuries and the leukocyte depletion in experimentally intoxicated animals.

Oral administration of piperine for the control of aflatoxin intoxication in rats.

Aflatoxins are mycotoxins that have important toxic effects on human and animal health, even if consumed at low doses. The oral administration of piperine (1.12 mg/kg) during 23 days in rats seemingly interfered with the toxicity of aflatoxins, decreasing hepatic injuries and the leukocyte depletion in experimentally intoxicated animals.