The action of anesthetics on excitable membranes: a quantum-chemical analysis.

Agin, D.; Hersh, Lawrence; Holtzman, Deborah

doi:10.1073/pnas.53.5.952

Cited by 81 publications

(35 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The conceptual roots of this non-empirical model go back to the work of Agin et al 41 and Cammarata et al [42][43][44][45] . Let us consider the state of thermodynamic equilibrium, and a 1:1 stoichiometry in the formation of the drug-receptor complex:…”

Section: Methods Models and Calculationsmentioning

confidence: 99%

Quantum Chemical Study of the Relationships Between Electronic Structure and Pharmacokinetic Profile, Inhibitory Strength Toward Hepatitis C Virus Ns5b Polymerase and HCV Replicons of Indole-Based Compounds

Vega

Alarcón

Gómez-Jeria

2013

J. Chil. Chem. Soc.

View full text Add to dashboard Cite

This paper uses newly developed and extended quantum chemical methods in an attempt to advance the knowledge of the relationship between the variation of several local atomic descriptors of the electronic structure and the variation of the inhibitory capacity of a group of reversible and irreversible inhibitors of hepatitis C virus NS5B polymerase. Good structure-activity relationships were obtained for both kinds of compounds. Some processes are charge-, orbital-and/or steric-controlled. The action mechanisms seem to be different for reversible and irreversible inhibitors. Also, good QSAR equations were obtained for the activities of these compounds in a cellular replicon assay and for pharmacokinetic profiles. The local atomic hardness seems to give a good account of the interaction of the drugs with apolar sites of the partner (enzyme, receptor, etc.). This is the first time that a purely quantum-chemical index is able to deal directly with this kind of interaction.

show abstract

Section: Methods Models and Calculationsmentioning

confidence: 99%

Quantum Chemical Study of the Relationships Between Electronic Structure and Pharmacokinetic Profile, Inhibitory Strength Toward Hepatitis C Virus Ns5b Polymerase and HCV Replicons of Indole-Based Compounds

Vega

Alarcón

Gómez-Jeria

2013

J. Chil. Chem. Soc.

View full text Add to dashboard Cite

show abstract

“…Ele pode representar forças dispersivas que ajudam a interação do ligante ao receptor 29 . Nesses casos esperar-se-ia um coeficiente positivo para MR. Alternativamente, uma vez que MR é, até um certo grau, uma medida de volume, ele pode medir a capacidade de o ligante distorcer a conformação do receptor para assim evitar a interação com o substrato.…”

Section: Descritores Físicos Da Estrutura Tridimensional (3d)unclassified

Validação lateral em relações quantitativas entre estrutura e atividade farmacológica, QSAR

Montanari¹,

Montanari²,

Gaudio³

2002

Quím. Nova

View full text Add to dashboard Cite

Recebido em 27/11/00; aceito em 6/7/01 COMPARATIVE QSAR OF ANTIMICROBIAL HYDRAZIDES. The comparative QSAR is a tool for validating any statistical model that seems to be reasonable in describing an interaction between a bioactive new chemical entity, BIONCE, and the biological system. In order to deeper the understanding of the relationships and the meaning of parameters within the model it is necessary some kind of lateral validation. This validation can be accomplished by chemical procedures using physicochemical organic reactions and by means of biological systems. In this paper we review some of such comparisons and also present a lateral validation between the same set of antimicrobial hydrazides acting against Saccharomyces cerevisiae yeast and Escherichia coli bacterium cells. QSARs are presented to shed light in this important way of stating that the QSAR model is not the endpoint, but the beginning.Keywords: QSAR; antimicrobial hydrazides; lateral validation. INTRODUÇÃOUma análise da interação vida-química facilmente resulta em benefícios à saúde humana porque se está tentando estimar os efeitos tóxicos necessários e não-necessários de fármacos, pesticidas e substâncias químicas naturais e industriais em várias formas e partes da vida. A interação é um processo de duas mãos: enquanto as substâncias químicas afetam processos na vida, organismos vivos apresentam suas armas para atacar xenobióticos.Uma maneira de compreender estas interações dá-se por relações entre a estrutura e a atividade, SAR. O principal aspecto inerente a esta observação vem da equação de Hammett ); k é uma constante de equilíbrio ou de rapidez, enquanto r é a medida da suscetibilidade da reação aos efeitos dos substituintes. Embora muitas dúvidas existam quanto ao funcionamento desta equação, a mesma trata de um dos conceitos de maior sucesso na elucidação dos mecanismos de reações.Taft ampliou a equação de Hammett com a inclusão do parâmetro estéreo, E s , que proporciona informações sobre a natureza do efeito do substituinte quando este estiver próximo do centro de reação. Hansch também ampliou a mesma equação quando introduziu o conceito de constantes lipofílicas em que sistemas biológicos são considerados.Não obstante, a simples obtenção de uma relação quantitativa entre a estrutura química e a atividade farmacológica, QSAR, pode significar muito pouco no que diz respeito à sua validade e significado. A validação estatística do modelo constitui apenas a primeira aproximação do significado enquanto que a correlação por validação lateral em termos de várias outras QSARs pode introduzir maior robustez ao modelo antes que ele seja testado na prática. Neste contexto, por exemplo, a busca das relações que apresentem reações de substituição nucleofílica com valores de r identificados em ordem crescente; a busca de todas as QSARs sobre bactérias; as reações em físico-química orgânica que contenham determinados coeficientes estéreos, E s ; a busca de todas as equações de QSAR em tópicos individuais como microssomos, cloroplastos, oxidorr...

show abstract

“…4 shows the relationship between log rx+y and log (K, Webb (11) classified the three types of interaction of two inhibitors by isobologram using fractional inhibition and empirical equations. In his treatment, summation is expressed by i1,2 = 'I + i2 -l i [3] where il,2 is the fractional inhibition when two [4] where A equals the inhibitor concentration and K is a constant.…”

Section: And 2 Are Indistinguishablementioning

confidence: 99%

“…This theory suggests that there are at least two separate modes of action among agents that show local anesthetic action: the predominant force of interaction of dissociable anesthetics is ionic, whereas the mode of action of undissociable local anesthetics is not. However, Agin et al (3) and Hersh (4) suggested that dissociable and undissociable local anesthetics may interact with living and model systems in an identical way.…”

mentioning

confidence: 99%

Combined effects of dissociable and undissociable local anesthetics upon ATP-induced firefly bioluminescence.

Kamaya¹,

Ueda²,

Eyring³

1976

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Combined effects of two drugs present simultaneously are usually expressed as summation, synergism or potentiation, and antagonism. When the sum of the effects of each drug present separately equals the combined effect of the two drugs present simultaneously, the action is called additive or summation. However, the expected value of the sum of each effect of drugs present alone has not been well defined. In this report, the theoretical value of the expected sum of each effect of two inhibitors is given and a graphical metho is presented to visualize summation, synergism, and antagonism. The inhibitory effects of a dissociable local anesthetic, tetracaine, and an undissociable local anesthetic, benzyl alcohol, upon a soluble firefly luminescent system were analyzed according to the above theory. The results clearly indicate that the action of these two classes of local anesthetics is pure additive or summation.Local anesthetics inhibit propagation of nerve impulses at synapses and at axons. A number of dissociable and undissociable compounds of diverse structure show local anesthetic activities.Clinically used local anesthetics possess a lipophilic benzene at one end and a tertiary amine on the other. The amine terminal is protonated to form a quaternary nitrogen and becomes highly hydrophilic with its positive charge. The extent of the positive charge is a function of the pka of the compound and the pH of the medium. At physiological pH these compounds exist in both uncharged and charged forms. It has been a matter of discussion as to which is the pharmacologically active form.Alcohols and volatile general anesthetics do not form charged molecules and show local anesthetic activities in excised nerve preparations. Barbiturates dissociate into negatively charged and uncharged molecules and show local anesthetic activities. The uncharged molecule should interact with nerve cells hydrophobically, whereas the charged molecule should bind to nerve cells electrostatically or by hydrogen bonding.Ritchie and Greengard (1) and later Narahashi et al. (2) proposed that local anesthetics penetrate the nerve cell membrane in its uncharged form and inhibit the nerve action by binding to the effector sites from the inside of the cell membrane in its positively charged form. This theory suggests that there are at least two separate modes of action among agents that show local anesthetic action: the predominant force of interaction of dissociable anesthetics is ionic, whereas the mode of action of undissociable local anesthetics is not. However, Agin et al. (3) and Hersh (4) suggested that dissociable and undissociable local anesthetics may interact with living and model systems in an identical way.We have previously shown that volatile general anesthetics (5) and dissociable local anesthetics (6) inhibit flash intensities of firefly luminescence in vitro. Firefly luciferin and luciferase can be solubilized from the tail lantern of fireflies and emit light in vitro when ATP is added. The flash intensity and total light o...

show abstract

The action of anesthetics on excitable membranes: a quantum-chemical analysis.

Abstract: rich nuclear RNA was formed in the rats which increased their performance linearly with time during learning. Some animals showed a nonlinear performance curve. The nuclear RNA formed in the neurons of these rats had a ribosomal type of base composition.

Cited by 81 publications

References 1 publication

Quantum Chemical Study of the Relationships Between Electronic Structure and Pharmacokinetic Profile, Inhibitory Strength Toward Hepatitis C Virus Ns5b Polymerase and HCV Replicons of Indole-Based Compounds

Quantum Chemical Study of the Relationships Between Electronic Structure and Pharmacokinetic Profile, Inhibitory Strength Toward Hepatitis C Virus Ns5b Polymerase and HCV Replicons of Indole-Based Compounds

Validação lateral em relações quantitativas entre estrutura e atividade farmacológica, QSAR

Combined effects of dissociable and undissociable local anesthetics upon ATP-induced firefly bioluminescence.

Contact Info

Product

Resources

About