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At least 19 recordsLinked to original sources
PubMed1989

Designer drugs.

Designer drugs are synthetic analogs of substances with known psychoactive properties. These analogs are dangerous due to their direct pharmacological effects and the presence of toxic by-products that occur during synthesis. Three groups of designer drugs are reviewed (fentanyl, meperidine, and methamphetamine analogs), and their psychoactive effects and clinical presentations are described.

Designer Drugs↗
PubMed1991

Substance abuse: the designer drugs.

Designer drugs, chemically altered compounds derived from federally controlled substances, have become a major cause of addiction and overdose deaths. These drugs include mescaline analogs, synthetic opioids, arylhexylamines, methaqualone derivatives and crack, a new form of cocaine. Sudden changes in mood, weight loss, depression, disturbed sleep patterns, deteriorating school or work performance, marital problems, and loss of interest in friends and social activities may be signs of drug addiction. Life-threatening complications of acute intoxication, such as hyperthermia, seizures, combative and psychotic behavior, and cardiorespiratory collapse, require prompt diagnosis and supportive intervention.

Clinical Protocols↗
PubMed1992

PLS-based quantitative structure-activity relationship for substituted benzamides of clebopride type. Application of experimental design in drug design.

The advantageous approach of using an experimentally designed training set as the basis for establishing a quantitative structure-activity relationship with good predictive capability is described. The training set was selected from a fractional factorial design scheme based on a principal component description of physico-chemical parameters of aromatic substituents. The derived model successfully predicts the activities of additional substituted benzamides of 6-methoxy-N-(4-piperidyl)salicylamide type. The major influence on activity of the 3-substituent is demonstrated.

Benzamides↗
PubMed1997

[The molecular patho-pharmacological studies for novel drug design by a principle of drug action in Japanese traditional Sino-medicine system].

In this study we carried out the pharmacological elucidation of the principle of drug action in the Japanese traditional Sino-medicine system, which could have contributed to the modern pharmacology and therapeutics through the discovery of a novel drug design and a new mechanism of drug action. The aim of this study was to focus on the elucidation of the supporting moiety in the drug design for the drug having affinity for a patho-receptor using a quite unique strategy and a new approach based on the natural products, Japanese traditional Sino-medicines relating to disease state, because of enormous clinical experiences with a long history. The characteristics of the pharmacological effects of Japanese traditional Sino-medicines were experimentally demonstrated by the following three key compartments, 1) the combined effect of drugs, 2) the selective activity of drugs to the disease state, 3) the possibility of individual symptomatological patterns (sho) evaluated by autonomic and immuno-pharmacological components. The success of the investigation on the principle of drug action of Japanese traditional Sino-medicines induced not only to obtain many novel compounds and unknown new mechanisms of drug action, but also to find a new salivary peptide for anti-hyperglycemics and a fresh mechanism of ACh receptor desensitization in neuromuscular synapse in the modern pharmacology. The results have brought the interchangeability of Japanese traditional Sino-medicine system to modern medicinal sciences, as described in the following contents, I. On the elucidation of a principle of drug action in the Japanese traditional Sino-medicine system. II. On the developmental frontier of drug design based on Japanese traditional Sino-medicines. III. On the interchangeability between the Japanese traditional Sino-medicine system and the modern medicinal sciences.

Animals↗
PubMed1998

Rational drug design approach for overcoming drug resistance: application to pyrimethamine resistance in malaria.

Pyrimethamine acts by selectively inhibiting malarial dihydrofolate reductase-thymidylate synthase (DHFR-TS). Resistance in the most important human parasite, Plasmodium falciparum, initially results from an S108N mutation in the DHFR domain, with additional mutation (most commonly C59R or N51I or both) imparting much greater resistance. From a homology model of the 3-D structure of DHFR-TS, rational drug design techniques have been used to design and subsequently synthesize inhibitors able to overcome malarial pyrimethamine resistance. Compared to pyrimethamine (Ki 1.5 nM) with purified recombinant DHFR fromP. falciparum, the Ki value of the m-methoxy analogue of pyrimethamine was 1.07 nM, but against the DHFR bearing the double mutation (C59R + S108N), the Ki values for pyrimethamine and the m-methoxy analogue were 71.7 and 14.0 nM, respectively. The m-chloro analogue of pyrimethamine was a stronger inhibitor of both wild-type DHFR (with Ki 0.30 nM) and the doubly mutant (C59R +S108N) purified enzyme (with Ki 2.40 nM). Growth of parasite cultures of P. falciparum in vitro was also strongly inhibited by these compounds with 50% inhibition of growth occurring at 3.7 microM for the m-methoxy and 0.6 microM for the m-chloro compounds with the K1 parasite line bearing the double mutation (S108N + C59R), compared to 10.2 microM for pyrimethamine. These inhibitors were also found in preliminary studies to retain antimalarial activity in vivo in P. berghei-infected mice.

Animals↗
PubMed1992

Computer-aided drug design: getting the best results.

There are two major stages in the design of drug molecules: lead-molecule development and lead-molecule optimization. Whereas a variety of computational chemistry and molecular modeling (CC/MM) techniques are now routinely and successfully applied to the optimization stage of drug design, the generation of initial lead compounds has proven a more difficult problem for the CC/MM approach. Only recently has the design of lead molecules by this route become a subject of active research. This article looks at the factors which must be considered carefully when incorporating CC/MM methods into different aspects of drug-design strategies.

Computers↗
PubMed1997

Serendipity meets precision: the integration of structure-based drug design and combinatorial chemistry for efficient drug discovery.

Structure-based drug design uses three-dimensional visualization of drug candidates bound to a target receptor to direct structural modifications that increase potency. This widely used approach is limited by the difficulty of accurately predicting drug-binding affinities from three-dimensional structures. The integration of structure-based drug design with combinatorial chemistry can overcome this limitation by providing an empirical understanding of drug-binding energies. This integration allows compound synthesis and evaluation in parallel, and also helps assure that the compounds produced have properties consistent with good bioavailability and safety.

Biological Availability↗
PubMed1996

A possible involvement of solvent-induced interactions in drug design.

We propose to study a new factor in designing new drugs. Most approaches to the drug design problem focus on the direct interactions between the drug and the corresponding target. We propose to study specific solvent-induced effects that can contribute to the binding Gibbs energy between the drug and its target. We estimate that these indirect effects will contribute significantly to the binding affinity and hopefully improve the clinical efficiency of the drugs.

Amino Acid Chloromethyl Ketones↗
PubMed1997

Retrometabolic approaches for drug design and targeting.

Retrometabolic drug design approaches incorporate targeting and metabolic considerations into the drug design process and represent a novel, systematic methodology for the design of safe, localized compounds. Two major design concepts aimed to increase the therapeutic index (the activity/toxicity ratio) of drugs were developed. Chemical delivery systems (CDS) are primarily used to allow targeting of the active biological molecules to specific target sites or organs based on predictable enzymatic activation. Brain-targeted delivery of different agents like estradiol or AZT was successfully achieved, and recent progresses include delivery of peptides using a complex strategy designated as molecular packaging. Sequential site- and stereospecific enzymatic activation of oxime/alkoxime precursors of beta-adrenergic antagonists allows their eye targeted delivery. Soft drug approaches are used to design new drugs by building in the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified subsequent to exerting its biological effects. Many examples are available to illustrate soft drug design, e.g., soft anticholinergics, soft b-blockers, soft antiinflammatory steroids. Special computer programs were developed that starting from a lead compound generate complete libraries of possible soft analogs and then help ranking these candidates based on molecular size/shape, electronic properties, predicted solubility/partition properties, and atomic charge distributions. Recent developments in the field are presented in a supplement to this issue.

Drug Delivery Systems↗
PubMed1997

Natural antisense RNA/target RNA interactions: possible models for antisense oligonucleotide drug design.

Current antisense oligonucleotides designed for drug therapy rely on Watson-Crick base pairing for the specificity of interactions between antisense and target molecules. However, thermodynamically stable duplexes containing non-Watson-Crick pairs have been formed with synthetic oligonucleotides. There are also numerous examples of non-canonical base pairs that participate in stable intra- and inter-molecular RNA/RNA pairing in prokaryotic and eukaryotic cells. Several natural antisense RNA/target RNA duplexes contain looped-out and bulged positions as well as non-canonical pairs as exemplified by formation of the Escherichia coli antisense micF RNA/ompF mRNA duplex. Secondary structures and the phylogenetic conservation of nucleotide sequences are well characterized in this system. Natural antisense/ target interactions may serve as models for determining possible and optimal antisense/target interactions in oligonucleotide drug design.

Bacterial Outer Membrane Proteins↗
PubMed1995

New approaches and technologies in drug design and discovery.

Traditional and novel approaches to drug design and screening techniques and strategies are described, and the potential benefits of new technologies are discussed. Sophisticated new approaches and technologies in the discovery and design of new drugs are replacing the traditional methods. Rational or structure-based methods of drug design and discovery that integrate techniques of x-ray crystallography, computational chemistry, and nuclear magnetic resonance spectroscopy are becoming the predominant methods. New technologies and methods for drug screening may yield significant savings in time and money, as well as increased diversity and specificity of lead compounds. Intense research activity is now being focused on small-molecule structure-based drug design, in which drugs would mimic the complex molecular interactions of natural proteins. The new approaches and technologies hold promise for dramatic therapeutic advances, particularly in the areas of transcriptionally active drugs and gene therapy. Rapid advances in drug design and screening, brought about through new technologies, may yield significant therapeutic advances and cost-effective therapies.

Biological Products↗
PubMed1995

Modelling of guanine-derivative--protein interaction complexes as a basis of drug design.

In rational drug design the study of protein-ligand-interactions is one of the most important approaches to get knowledge of SAR. On this study N2-Phenylthioguanines were synthesized by Schiemann reaction from thioguanine followed by a substitution of the fluorine by aniline-derivatives. The activity of these HSV1 TK inhibitors was determined by kinetic measurements of thymidine phosphorylation. The N2-Phenylthioguanines gave the same activity as the oxoanalogues. Interaction energies between thymidine and HSV1 TK were measured by microcalorimetry. Results of the measurement showed negative delta G and delta H values which indicates that the binding of the natural substrate occurs spontaneously and is enthalpy driven.

Calorimetry↗
PubMedDate not supplied

Rational drug design: the proteinase inhibitors.

Human immunodeficiency virus (HIV) proteinase is a promising target for the rational development of drugs against the acquired immunodeficiency syndrome (AIDS), since this enzyme is necessary for viral maturation, and its inhibition could lead to cessation of viral replication. Rational drug design combines chemical synthesis of compounds with structure determination methods, including protein crystallography. When the crystal structure of the HIV proteinase was determined, many research laboratories began designing drugs that would be effective inhibitors of the enzyme, and many such inhibitors were produced. Once that work was initiated, refined, and completed in the laboratory, other issues, such as specificity and bioavailability, became important. The clinical utility of such compounds is the final and most important consideration. Analysis of many agents for which structural formulas have been determined, and comparison of such formulas, provide valuable lessons for the continuing work on this enzyme and for future programs of rational drug design.

Amino Acid Sequence↗