Investigation of the Interaction Mode of Phenothiazine Neuroleptics with α1-Acid Glycoprotein

Miyoshi, Tetsu; Sukimoto, Katsuaki; Otagiri, Masaki

doi:10.1111/j.2042-7158.1992.tb14358.x

Cited by 26 publications

(26 citation statements)

References 26 publications

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“…Since amino electron density correlates with pK a values of the drugs, they postulated that a negatively charged region on the protein was stabilizing the binding of basic drugs by interacting with their protonated amino termini. Their model was likewise consistent with previous observations that the pK a values of phenothiazines correlated with their apparent affinities for unfractionated AGP (Miyoshi et al, 1992). However, for the LAs reported here, there was no correlation between pK a and affinity (Fig.…”

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confidence: 93%

“…For the two series of local anesthetics, the linear alkyl amino homologs of lidocaine and the piperidine ring-containing homologs of mepivacaine, we found a linear relationship (r 2 ϭ 0.82) between ⌬G (dissociation) for AGP binding and the octanol:buffer partition coefficient of the neutral drug species. The strong correlation between hydrophobicity and the affinity for the LAs is in accord with studies showing that generalized hydrophobicity is a major determinant of binding for other drug classes, including basic drugs such as antihistamines and antihypertensives (Kaliszan et al, 1996), diazepines (Maruyama et al, 1992), and phenothiazines (Miyoshi et al, 1992), as well as acidic drugs such as coumarin anticoagulants (Maruyama et al, 1990). That the same linear correlation holds for both homologous series, each with a different conformation of carbons around the amino nitrogen, implies that this hydrophobic interaction is relatively forgiving, suggesting that the binding site is a broad hydrophobic surface or a flexible pocket that can accommodate ligands with a range of sizes.…”

Section: Discussionsupporting

confidence: 76%

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Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α1-Acid Glycoprotein

Taheri

Cogswell²,

Gent³

et al. 2003

The Journal of Pharmacology and Experimental Therapeutics

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Understanding the interaction of local anesthetics (LAs) with plasma proteins is essential to understanding their systemic pharmacology and toxicology. The molecular determinants of LA binding to the major variant (F1*S) of human ␣ 1 -acid glycoprotein (AGP) were therefore investigated spectrofluorometrically using whole AGP and a novel, F1*S variant-selective probe previously developed in our laboratory. Equilibriumcompetitive displacement of this probe by LAs, observed by the recovery of AGP's fluorescence as the quenching probe was displaced from its high-affinity site, was characterized by inhibitory dissociation constants for the various LAs. The importance of electrostatic factors was assessed by examining the pH dependent binding of an ionizable LA, lidocaine, using the quaternary lidocaine derivative triethylammonium chloride] to control for pH dependent ionization of AGP. Uncharged lidocaine bound with at least 8 times the affinity of protonated lidocaine (K D ϭ 4.0 Ϯ 0.6 M and Ͼ32 M, respectively). This result is inconsistent with the current model of the AGP-binding site, which depicts a buried pocket having a negatively charged region that interacts with the amino termini of basic drugs. Consistent with the model, however, two sets of structurally homologous LAs (mepivacaine, ropivacaine, bupivacaine, and lidocaine, RAD-240, RAD-241, RAD-242, L-30, W-6603) demonstrated a strong positive correlation between hydrophobicity (measured as the octanol:buffer partition coefficient of the neutral species) and their free energies of dissociation. Given that the tertiary structure of AGP has proven refractory to resolution, these structure-activity studies should contribute to understanding the nature of the binding site on this important protein.Understanding the interaction of local anesthetics with plasma proteins is essential to predicting their systemic pharmacology and toxicology. Many basic drugs, including local anesthetics (LAs) and class I antiarrythmics, are bound in blood principally or in part by AGP (Routledge, 1986;Stanski and Watkins, 1986;Wood, 1986;Kremer et al., 1988). The binding of a drug to a plasma protein reduces its free fraction in serum, thus reducing its availability for active uptake or diffusion into surrounding tissue and significantly influencing its pharmacokinetics, toxicity, etc. (Wood, 1986).For example, the local anesthetic bupivacaine binds tightly to AGP (with K D ϭ 1 M) (Essassi et al., 1989), and this binding may mitigate the systemic toxicity of bupivacaine (Wulf et al., 1991;Mazoit et al., 1996).Indeed, altered pharmacokinetics have been observed following the binding of AGP to the LAs lidocaine and cocaine, and the same holds true with other clinically relevant amphipathic amines: amitriptyline, chlorpromazine, nicardipine, and verapamil (Benet and Hoener, 2002). For example, AGP concentration has been shown to correlate inversely with the free fraction of the LA ropivacaine 60 min after epidural injection (Porter et al., 2001). Also, one of the AGP variants...

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confidence: 93%

Section: Discussionsupporting

confidence: 76%

Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α1-Acid Glycoprotein

Taheri

Cogswell²,

Gent³

et al. 2003

The Journal of Pharmacology and Experimental Therapeutics

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“…1,[4][5][6][7][8] Two common methods that have been used in evaluating the binding of drugs to albumin include equilibrium dialysis and ultrafiltration. 9,10) These methods are laborious and time consuming and the results at times are not reproducible. However, these conventional methods are often inapplicable to the analyses of strongly bound drugs because of technical problems such as drug adsorption on the membrane and the leakage of bound drug through membrane.…”

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confidence: 99%

Spectroscopic Studies and Life Time Measurements of Binding of a Bioactive Compound to Bovine Serum Albumin and the Effects of Common Ions and Other Drugs on Binding

Shaikh

Seetharamappa

Ashoka

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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The interaction of a drug with blood components influences its bioavailability and can affect the functions of several biomolecules.1) Clinical effect of the plasmatic level of a drug is an important pharmacological parameter determined by drug absorption, distribution and elimination. Serum albumins, the most abundant proteins in circulatory system of a wide variety of organisms, have been well studied for many years. They account for about 60% of the total protein corresponding to a concentration of 42 g l Ϫ1 2,3) and provide about 80% of osmotic pressure of blood.2) Albumins have been used as a model protein for diverse biophysical, biochemical and physicochemical studies 3) to gain general fundamental insights into drug-protein binding. The remarkable binding properties of albumin accounts for the central role it can play in both the efficacy and rate of delivery of drugs. Several classes of drugs including tranquillizers, anti-coagulants and general anesthetics are transported in the blood while bound to albumin. This kind of work has stimulated many researchers to carry out the research on the nature of the drug binding sites and investigations of whether natural metabolites, drugs and fatty acids compete with one another for binding to the protein. 4) These results provide salient information of the structural features that determine the therapeutic effectiveness of drugs, and hence become an important research field in chemistry, life sciences and clinical medicine. 1,[4][5][6][7][8] Two common methods that have been used in evaluating the binding of drugs to albumin include equilibrium dialysis and ultrafiltration.9,10) These methods are laborious and time consuming and the results at times are not reproducible. However, these conventional methods are often inapplicable to the analyses of strongly bound drugs because of technical problems such as drug adsorption on the membrane and the leakage of bound drug through membrane. To overcome these problems, we have employed fluorimetric, lifetime measurements, absorption and circular dichroism methods to investigate the mode of binding of NIM with BSA in the present investigation.Nimesulide (NIM), chemically N-(4-nitro-2-phenoxyphenyl) methanesulphonamide, is a relatively new non-steroidal antiinflammatory (NSAID), antipyretic and analgesic drug. 11)It is widely used for the treatment of inflammatory conditions associated with rheumatoid arthritis, respiratory tract infections, soft tissue and oral cavity inflammations. The therapeutic effect of NSAIDs is the result of their ability to inhibit prostaglandin synthesis via inhibition of cyclooxigenase. The analgesic potency of NIM is similar to that of ibuprofen and indomethacin. Nonetheless, NIM has shown a higher antipyretic potency relatively than indomethacin, ibuprofen, aspirin and paracetamol. Because of its biological importance, we thought of investigating the mechanism of binding of NIM with BSA by fluorescence, UV-visible absorption, circular dichroism and fluorescence lifetime measurements. The ener...

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“…Two common methods that have been used in evaluating the binding of drugs to albumin include equilibrium dialysis and ultrafiltration. 7) These methods are laborious and time consuming and the results, at times, are not reproducible. More over, these conventional methods are often inapplicable to the analyses of strongly bound drugs because of technical problems such as drug adsorption on the membrane and the leakage of bound drug through membrane.…”

mentioning

confidence: 99%

Spectroscopic Studies on the Mode of Interaction of an Anticancer Drug with Bovine Serum Albumin

Seetharamappa

Kamat

2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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Investigation of the Interaction Mode of Phenothiazine Neuroleptics with α1-Acid Glycoprotein

Cited by 26 publications

References 26 publications

Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α1-Acid Glycoprotein

Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α1-Acid Glycoprotein

Spectroscopic Studies and Life Time Measurements of Binding of a Bioactive Compound to Bovine Serum Albumin and the Effects of Common Ions and Other Drugs on Binding

Spectroscopic Studies on the Mode of Interaction of an Anticancer Drug with Bovine Serum Albumin

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