Receptor-binding studies using cloned human muscarinic receptors (M1-M4 subtypes) were performed on newly synthesized soft anticholinergics (F-828, F-838, SGM, SGE, SA-A) that are isosteric/ isoelectronic analogs of glycopyrrolate. The... more
Receptor-binding studies using cloned human muscarinic receptors (M1-M4 subtypes) were performed on newly synthesized soft anticholinergics (F-828, F-838, SGM, SGE, SA-A) that are isosteric/ isoelectronic analogs of glycopyrrolate. The receptor binding pK(i) values of the new soft drugs were in the 5.5-9.5 range; with the majority being in the 7.0-8.5 range. As previously observed for similar structures, the pK(i) values tended to decrease with increasing molecular size, and with the introduction of three structural indicator variables, a QSAR equation accounting for close to 75% of the variability could be established. Confirming the known stereospecificity of these receptors, pure 2R isomers were found more active than the corresponding isomeric mixtures. In agreement with soft drug design principles, acid metabolites (SA-A) were found considerably less active than their parent esters. The more active, 2R isomer of SA-A showed some muscarinic subtype selectivity (M3/M2), which was...
Research Interests: Algorithms, Chemistry, Kinetics, Medicine, Humans, and 15 moreAnimals, Male, Quantitative Structure Activity Relationship, Pharmazie, Receptor, Muscle contraction, Rabbits, Pupil, Metabolite, Ileum, Cholinergic antagonists, Mydriatics, Guinea pigs, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
The object of the present work was to investigate the difference in the metabolism of the phosphonate derivatives of primary or secondary hydroxyl groups. To study the phosphorolytic cleavage of such P-O bonds, zidovudine (AZT)... more
The object of the present work was to investigate the difference in the metabolism of the phosphonate derivatives of primary or secondary hydroxyl groups. To study the phosphorolytic cleavage of such P-O bonds, zidovudine (AZT) hexanoyloxymethyl-methylphosphonate (HOM-AZT-P), an ester of a primary OH functionality, and methyl-pivaloyloxymethyl-testosterylphosphonate (POM-T-P), an ester of a secondary OH functionality, were prepared. The actions of pure enzymes such as alkaline phosphatase and phosphodiesterase on the corresponding phosphonate compounds (AZT-P and T-P) were investigated at various pH values. The phosphonate derivative of the secondary hydroxyl group of testosterone proved completely resistant to such phosphorolytic attacks, and release of free testosterone could not be detected. The phosphonate derivative of the primary hydroxyl group of zidovudine proved resistant to phosphodiesterase, but not to alkaline phosphatase, and in this second case, release of free zidovud...
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Research Interests: Chemistry, Metabolism, Medicine, Humans, Animals, and 15 moreDrug Design, Article, Partition Coefficient, Guinea Pig, Lipophilicity, Correlation coefficient, Linear Regression, Muscarinic Receptor, Protein Binding, Drug Stability, Anticholinergic, Ileum, Cholinergic antagonists, Guinea pigs, and Pharmacology and pharmaceutical sciences
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Research Interests: Thermodynamics, Chemistry, Water, Molecular Dynamics, Solvation, and 14 moreMathematical Analysis, Vapor Pressure, Partition Coefficient, Solubility, Free Energy, Hydrogen Bond, Hydrophobicity, Water soluble polymers, Water Soluble Fertilizers, Molecular Size, Solvent, Physical Properties, Vaporization, and Boiling point
As a general review for the 7th Retrometabolism-Based Drug Design and Targeting Conference, recent developments within this field are briefly reviewed with various illustrative examples from different therapeutic areas. Retrometabolic... more
As a general review for the 7th Retrometabolism-Based Drug Design and Targeting Conference, recent developments within this field are briefly reviewed with various illustrative examples from different therapeutic areas. Retrometabolic drug design incorporates two major systematic approaches: the design of soft drugs and of chemical delivery systems (CDS). Both aim to design new, safe drugs with an improved therapeutic index by integrating structure-activity and structure-metabolism relationships; however, they achieve it by different means: whereas soft drugs are new, active therapeutic agents that undergo predictable metabolism to inactive metabolites after exerting their desired therapeutic effect, CDSs are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps.
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Research Interests: Algorithms, Biotechnology, Biology, Drug delivery, Medicine, and 15 morePregnancy, Humans, Computer Simulation, Female, Animals, Feasibility Studies, Immunosuppression, Drug Delivery Systems, Pharmazie, Cell Transplantation, Microspheres, Lactic Acid, Glucocorticoids, Immunosuppressive Agents, and Pharmacology and pharmaceutical sciences
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Introduction Adverse side effects of systemic immunosuppression limit the indication of islet transplantation to severe cases of diabetes. Transplantation of syngeneic islets corrects diabetes into prevascularized, subcutaneous biohybrid... more
Introduction Adverse side effects of systemic immunosuppression limit the indication of islet transplantation to severe cases of diabetes. Transplantation of syngeneic islets corrects diabetes into prevascularized, subcutaneous biohybrid devices (BHD). Aim of the present study was to evaluate the effects of localized immunosuppression on allogeneic islet allograft survival into BHD with an infusion port. Methods Wistar Furth (RT1u) rat islets were implanted into a prevascularized, subcutaneous BHD (Converge Biotech) in diabetic ...
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... While it was long obvious that all such intermolecular interaction-related physicochemicalproperties (eg, T b , H vap , log γ, log ρ gas , σ, log P, log ρ w , log K CD ) have to be connected, it is for the first time that they could... more
... While it was long obvious that all such intermolecular interaction-related physicochemicalproperties (eg, T b , H vap , log γ, log ρ gas , σ, log P, log ρ w , log K CD ) have to be connected, it is for the first time that they could be placed within the framework of a unified and ...
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Dexanabinol and other synthetic 6aS-trans cannabinoids are devoid of cannabimimetic activity, as they do not have affinity toward cannabinoid receptors. On the other hand, these compound bind to the NMDA receptor and possess... more
Dexanabinol and other synthetic 6aS-trans cannabinoids are devoid of cannabimimetic activity, as they do not have affinity toward cannabinoid receptors. On the other hand, these compound bind to the NMDA receptor and possess neuroprotective properties. A ranking of 6aS-trans cannabinoids based on their NMDA receptor binding affinity and by using a variety of calculated properties included in a fully computerized expert system has been attempted. The results of the study indicate that either the present isosteric-isoelectronic-based ranking criteria is not adequate to reproduce NMDA receptor binding or that some other members of the series rather than dexanabinol are the true lead compounds of 6aS-trans cannabinoids.
Research Interests: Chemistry, Electrochemistry, Medicine, Neuroprotection, Cannabinoids, and 12 moreBiological Sciences, Environmental Sciences, expert System, CHEMICAL SCIENCES, Theoretical Models, Synthetic Cannabinoids, Structure activity Relationship, Cannabinoid, Cannabinoid Receptor, Binding affinity, NMDA receptor, and binding sites
A remarkably simple, molecular size-based model developed to predict octanol-water partition coefficients for organic compounds is tested on a set of 188 neutral peptides with available experimental partition data. Despite using only two... more
A remarkably simple, molecular size-based model developed to predict octanol-water partition coefficients for organic compounds is tested on a set of 188 neutral peptides with available experimental partition data. Despite using only two parameters, it gives a promising correlation (r2 = 0.914; sigma = 0.455, F = 1978.0), and predictions are in a realistic range even for larger peptides (cyclosporin, melanotan, sandostatin) where common, overparametrized fragment methods become quite unreliable. Ion-pair partitioning and the extraction constant formalism is briefly reviewed to describe the sigmoidal lipophilicity profile of ionizable, nonzwitterionic peptides. It seems possible to extend the present model to estimate apparent partition coefficients measured around neutral pH and physiological conditions for monoionic peptides; however, as no standard conditions are yet defined and only relatively small number of experimental data are available, the situation here is more complex.
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ABSTRACT
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Research Interests: Computer Science, Chemistry, Technology, Computer Aided Design, Medicine, and 14 moreDrug, Biological Sciences, Software, Humans, Animals, Drug Design, Molecular Biotechnology, Biotransformation, Malathion, Oxidation-Reduction, Biochemistry and cell biology, Pharmaceutical preparations, Medical and Health Sciences, and design principle
After a brief review of a number of issues related to the enzymatic hydrolysis of carboxylic esters, scuh as interspecies variability, mechanism, stereospecificity, and activation energy, and after and overview of relevant aspects related... more
After a brief review of a number of issues related to the enzymatic hydrolysis of carboxylic esters, scuh as interspecies variability, mechanism, stereospecificity, and activation energy, and after and overview of relevant aspects related to the quantitative modeling of steric effects, the results of a recently developed quantitative structure-metabolism relationship model are discussed. They were obtained for in vitro human blood enzymatic hydrolysis of noncongener esters by introduction of the inaccessible solid angle as a novel measure of steric hindrance.
Research Interests: Chemistry, Kinetics, Biology, Enzyme Inhibitors, Medicine, and 15 moreHumans, Animals, Drug Design, Enzyme, Enantioselectivity, Molecular Conformation, Hydrolysis, Pharmacokinetic Studies, Bentham Science Publishers, Noncongener Esters, Esterase Activity, Liposomal Phosphatidylcholine, Multiple halosubstituted, Enzymatic hydrolysis, and binding sites
Soft drug design represents a new approach aimed to design safer drugs with an increased therapeutic index by integrating metabolism considerations into the drug design process. Soft drugs are new therapeutic agents that undergo... more
Soft drug design represents a new approach aimed to design safer drugs with an increased therapeutic index by integrating metabolism considerations into the drug design process. Soft drugs are new therapeutic agents that undergo predictable metabolism to inactive metabolites after exerting their therapeutic effect. Hence, they are obtained by building into the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified. In an attempt to systematize and summarize the related work done in a number of laboratories, including ours, the present review presents an overview of the general soft drug design principles and provides a variety of specific examples to illustrate the concepts. A number of already marketed drugs, such as esmolol, remifentanil, or loteprednol etabonate, resulted from the successful application of such design principles. Many other promising drug candidates are currently under investigation in a variety of fields including possible soft antimicrobials, anticholinergics, corticosteroids, beta-blockers, analgetics, ACE inhibitors, antiarrhythmics, and others. Whenever possible, pharmacokinetic and pharmacodynamic properties are briefly summarized and compared to those of other compounds used in the same field.
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Various cell-penetrating peptides have been discovered recently that can translocate across plasma membranes and can even carry large cargo molecules into the cells. Because under physiological conditions most of these peptides carry... more
Various cell-penetrating peptides have been discovered recently that can translocate across plasma membranes and can even carry large cargo molecules into the cells. Because under physiological conditions most of these peptides carry considerable positive charges due to the presence of basic amino acids such as arginine, we decided to investigate whether molecular transporters composed of permanently charged side-chains also possess such cell penetrating ability. Arginine-rich oligomers that have a backbone with increased flexibility due to incorporation of non-α-amino acids (ε-aminocaproic acid) have been found to be effective molecular transporters. Here, we report the preparation of analogue structures by replacing the arginine residues with the quaternary form of a novel redox amino acid (Nys+) that contain a trigonelline moiety; it has already been shown possible to replace the original basic amino acid side-chain of neuropeptides without significant activity-loss due to the su...
Research Interests: Chemistry, Medicine, Humans, Circular Dichroism, Pharmacology and Clinical pharmacy, and 12 moreAmino Acids, Fourier transform infrared spectroscopy, HeLa cells, Arginine, Side-chain, Transporter, Amino Acid Profile, Protein Conformation, Structure activity Relationship, Drug Carriers, Fluorescein, and Pharmacology and pharmaceutical sciences
To reduce the possibility of systemic side-effects in locally administered anticholinergics, two new N-substituted glycopyrrolate analogues designed using soft drug design approaches have been synthesized and evaluated in vitro and in... more
To reduce the possibility of systemic side-effects in locally administered anticholinergics, two new N-substituted glycopyrrolate analogues designed using soft drug design approaches have been synthesized and evaluated in vitro and in vivo. Because stereospecificity is known to be important at muscarinic receptors, the new compounds SGM and SGE also have been prepared as their pure 2R isomers, 2R-SGM and 2R-SGE, by starting from optically pure (-)-cyclopentylmandelic acid, and the corresponding isomers were indeed found to be more active. The new soft glycopyrrolates were chemically more stable under acidic conditions, and the ethyl esters SGE were more stable than the methyl esters SGM. The new compounds were also found to be quite susceptible to extrahepatic metabolism, having half-lives of 20–30 min in rat plasma (in vitro), consistent with their soft nature. Binding studies at human muscarinic receptors (M1−M4) and guinea-pig ileum assays found 2R-SGM and 2R-SGE to have potencie...
Research Interests: Pharmacology, Chemistry, Medicine, Cell line, In Vitro, and 15 moreHumans, Pharmacology and Clinical pharmacy, Animals, Male, Drug Design, Molecular cloning, In Vivo, Muscle contraction, Rabbits, Pupil, Drug Stability, Cholinergic antagonists, Mydriatics, Guinea pigs, and Pharmacology and pharmaceutical sciences
By an extension of our simple, molecular size-based model recently developed to describe octanol-water partition coefficients, we were able to obtain an entirely structure-based model that seems well suited to describe human skin... more
By an extension of our simple, molecular size-based model recently developed to describe octanol-water partition coefficients, we were able to obtain an entirely structure-based model that seems well suited to describe human skin permeability data. The corresponding equations not only eliminate the physicochemical interrelatedness of the parameters of the original Potts & Guy approach that was obtained from similar considerations, but also maintain its elegant simplicity and are consistent with a basic physicochemical model of the related phenomena. As the new model is structure based and fully computerized, it allows direct estimation of skin permeability for any molecule of known structure without the need to obtain octanol-water partition coefficients or other experimental data.
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The N-acetylation of the noncompetitive AMPA antagonist talampanel (TLP) represents a route of varying significance in various species. For a detailed analysis in humans, plasma concentrations of TLP and its N-acetyl metabolite (NAc-TLP)... more
The N-acetylation of the noncompetitive AMPA antagonist talampanel (TLP) represents a route of varying significance in various species. For a detailed analysis in humans, plasma concentrations of TLP and its N-acetyl metabolite (NAc-TLP) were measured for up to 48 h after administration of a single oral dose of 75 mg in 28 healthy volunteers following genotyping for the N-acetyltansferase NAT2 isozymes (alleles NAT2*4, *5, *6, and *7). Unified parent-metabolite pharmacokinetic (PK) models that allowed three different rates of acetylation were used to simultaneously fit plasma levels for both the parent drug and its metabolite following genotype-based classification as slow, intermediate, or fast acetylator. A perfect correspondence was found between the phenotype inferred from genotyping and the phenotype determined by using plasma metabolite-to-parent molar ratios indicating that this route of metabolism is indeed mediated by NAT2. Linear parent-metabolite PK models (first-order input, first-order elimination through two parallel routes one of which is through a metabolite with polymorphic rate of formation) gave adequate and sufficiently consistent fit. Parameters obtained suggest that for TLP in humans, N-acetylation represents only about 1/4th of the total elimination even in true (*4/*4 homozygous) fast acetylators, acetylation is about 8-12 times faster in fast and 3-6 times faster in intermediate acetylators than in slow acetylators, and the N-acetyl metabolite is eliminated faster than the parent drug. Such PK models can provide quantitative estimates of relative in vivo metabolism rates for routes catalyzed by functionally polymorphic enzymes.
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Abstract: The present invention provides highly porous, biocompatible and biostable scaffold constructs for improving overall cell engraftment, survival, function and long-term viability. These scaffolds can provide mechanical protection... more
Abstract: The present invention provides highly porous, biocompatible and biostable scaffold constructs for improving overall cell engraftment, survival, function and long-term viability. These scaffolds can provide mechanical protection to implanted cells, afford retrievability from a subject, and allow for both intra-device vascularization and a means to spatially distribute the cells within the device. The scaffold surface or material may be modified with one or more different adhesion proteins and optionally other biological factors for ...