The site of general anaesthesia and cytochrome P450 oxygenases: similarities defined by straight chain and cyclic alcohols

LaBella, Frank S.; Chen, Q M; Stein, Douglas; Queen, Gary

doi:10.1038/sj.bjp.0701006

Cited by 10 publications

(2 citation statements)

References 39 publications

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“…C 6 –C 13 carbon length straight alcohols of increasing n -alkyl chain length and molecular weight (Da) have been shown to exert concentration dependent inhibitory effects on the P450 cytochrome monooxygenase activity (aminopyrine demethylase) in vitro , with disassociation constants (K i ) ranging between 1.3 mM (C 6 , hexanol) and 2.66 mM (C 13 , tridecanol) with uM inhibition by dodecanol (C 12 ; 35 uM) [ 30 , 31 ] , indicative of a cutoff of enzyme activity at a chain length of between 12- and 13-C (vdWD: 0.744–0.762 nm) at the cell membrane channel pore vdWD, in which case C 2 -ethanol (mM) is non-exothermic (-ΔT; ᵒC) as compared to C 16 -hexadecan-1-ol (C 16 H 34 O, cetyl; uM) with inhibitory effect at a CM receptor [ 32 ] . Therefore, the decrease in cell P eff (0.153–0.160) due to C 2-4 halogenate-mediated inner mitochondrial membrane (IMM) micro-compliance alteration is attributable to resultant ATP deficit, and synergistic with the affinity perturbation of CM by larger poly-substituted alcohols (ie C 16 H 34 O 4 isomers) [ 33 ] , which are convergent mechanisms of decreased cell micro-compliance (-Δ C micro ) initially, prior to protein adduct effects on C micro .…”

Section: Discussionmentioning

confidence: 99%

Pressure regulated basis for gene transcription by delta-cell micro-compliance modeled in silico: Biphenyl, bisphenol and small molecule ligand models of cell contraction-expansion

Sarin¹

2020

PLoS ONE

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Molecular diameter, lipophilicity and hydrophilicity exclusion affinity limits exist for small molecule carrier-mediated diffusion or transport through channel pores or interaction with the cell surface glycocalyx. The molecular structure lipophilicity limit for non-specific carriermediated transmembrane diffusion through polarity-selective transport channels of the cell membrane is L external structure � H polar group-1 of � 1.

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Section: Discussionmentioning

confidence: 99%

Pressure regulated basis for gene transcription by delta-cell micro-compliance modeled in silico: Biphenyl, bisphenol and small molecule ligand models of cell contraction-expansion

Sarin¹

2020

PLoS ONE

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“…unlike most enzymes (PKC is also an exception to this generalisation), this complex is inhibited by various anaesthetic agents. Figure 16 shows that in a series of compounds of the alkan-1-ol class (a saturated aliphatic chain with the alcohol on the terminal carbon) all members (at least up to C=14) inhibit P 450 and that (up to C=11), there is increasing potency as chain length increases 31 . Furthermore, there is a strong parallel between the inhibitory concentrations (open circles) and anaesthetic potency (filled circles).…”

Section: Enzymatic Actions Generallymentioning

confidence: 99%

Some Scientific Reflections on Possible Mechanisms of General Anaesthesia

2009

Anaesth Intensive Care

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The challenge to achieve a gestalt understanding of general anaesthesia is really dependent upon an understanding of the elusive concept of consciousness. Until very recently, anaesthesia has been understood to depend fundamentally on the lipid solubility of anaesthetic agents, unsurprisingly a misleading view which has followed from the greater simplicity of lipid chemistry compared with protein chemistry and, it is contended here, from a serious misunderstanding of the older experimental data. Nonetheless, because an over-simplistic view of lipids pertains in much pharmacological thinking about anaesthesia, this paper devotes some attention to potentially relevant aspects of lipid function and also to concepts of anaesthesia which are based on the properties of intracellular and extracellular water. It is argued that the more correct pharmacological explanation is likely to be action at hydrophobic sites of crucial functional molecules, most plausibly protein molecules: empirical data which support such actions are presented and considered.Anaesthetic actions on a range of such proteins are discussed, with the emphasis on general neurophysiological principles, with the intent of avoiding the mire into which detailed consideration of actions at specific sites of putative function in the central nervous system can lead. Those experimentally-documented actions include influences on the proteins which constitute the Na + -ion conductance channels in axonal membranes (which are the basis for action potentials); on the Ca 2+ -ion channels which are crucial for neurotransmitter secretion from nerve terminals; on the properties of the ion channels in the post-synaptic membranes of the neurons which are the targets for transmitter action; on components of the "second messenger" systems of target neurons; as well as actions on metabolically significant enzymes (notably cytochrome P450).The overall argument is that the concept of anaesthetic actions on lipids should be abandoned in favour of one which is consistent with the general pharmacological principle of drug action at specific receptor sites, i.e. a targeted action at unique loci on relevant proteins.

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History of Quantitative Structure–Activity Relationships

Selassie

Verma

2010

Burger's Medicinal Chemistry and Drug Discovery

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This chapter gives an overview of the historical development of the quantitative structure–activity relationship (QSAR) paradigm with a particular emphasis on the past 50 years. Parameters used to formulate various mathematical models are described as originally delineated. Refinement and fine‐tuning of these variables as they evolved and were utilized, is also described. They are sequestered according to their electronic, hydrophobic, steric, and molecular orbital properties. Recent emphasis on molecular descriptors in high‐throughput screening mandates their inclusion in this chapter. Various QSAR models spanning two‐dimensional space to six‐dimensional space are described and applied to various chemicobiological systems in isolated receptors, in vitro systems and in vivo systems. The presence of outliers in QSAR is also discussed in this chapter. Validation methods that are pertinent to QSAR model development are also addressed. The development of databases that encapsulate significant data on variables and models that allow for rapid retrieval, usage, and validation of chemical reactions and biological interactions is included in this analysis of QSAR.

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The site of general anaesthesia and cytochrome P450 oxygenases: similarities defined by straight chain and cyclic alcohols

Cited by 10 publications

References 39 publications

Pressure regulated basis for gene transcription by delta-cell micro-compliance modeled in silico: Biphenyl, bisphenol and small molecule ligand models of cell contraction-expansion

Pressure regulated basis for gene transcription by delta-cell micro-compliance modeled in silico: Biphenyl, bisphenol and small molecule ligand models of cell contraction-expansion

Some Scientific Reflections on Possible Mechanisms of General Anaesthesia

History of Quantitative Structure–Activity Relationships

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