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PubMed1992

'Designer drugs'. Recognizing and managing their toxic effects.

"Adam," "Eve," "ecstasy," "China white." Illicit street drugs such as these are called designer drugs because they are designed to elicit certain effects and to bypass legal classification. Unfortunately, use and abuse of such substances can lead to serious medical problems and even death. Drs Sternbach and Varon describe the best-known compounds and discuss clinical characteristics and management of designer drug intoxication.

Amphetamines↗
PubMed1989

[Neurologic complications of drug addiction. General aspects. Complications caused by cannabis, designer drugs and volatile substances].

When a patient presents a neurological disorder, it is important to consider drugs is a possible cause. The risk to suffer neurological complications by drugs is unknown. It is difficult to calculate the number of drug addicts or the number of occasional drug users. It is important take into account that some patients are using more than one drug. The acute use of cannabis induces important changes in cognition and psychomotor performance. No signs of neurotoxicity were found in chronic marihuana users. Some "designer drugs" can induce neurotoxicity. MDMA, that have hallucinogenic activity, is a neurotoxin in animals. MPTP kill dopaminergic neurons in the substantia nigra, inducing Parkinson's disease. Volatile substances containing toluene or n-hexane are usually abused by young people. They can produce neurological damage when are used chronically (p. ex. cerebral atrophy or peripheral neuropathies).

Cannabis↗
PubMed2004

A new trend in drugs-of-abuse; the 2C-series of phenethylamine designer drugs.

OBJECTIVE: To collect data related to phenethylamine drugs-of-abuse of the 2C-series, to review possible health risks of their use and to discuss legal counter actions of authorities in the European Union (EU). SETTINGS: Dutch smartshops. METHODS: In the period of 1994-2002, all products that were claimed to contain synthetic drugs and sold in the smartshops, were purchased. The contents were analysed using analytical chemical technologies such as gas chromatography/mass spectrometry and nuclear magnetic resonance. Additionally, using computerised searches in relevant databases and checking cross-references, literature and documents were screened for scientific based information. RESULTS: All purchased products proved to be tablets, of which most of them contained one of the phenethylamine designer drugs 2C-B, 2C-T-2 or 2C-T-7. The different drugs were introduced on the Dutch smartshop market within time intervals of approximately three years. The information that was supplied on leaflets and accompanied the products sometimes appeared to be extensive, but was partly misleading and incorrect. Besides that, scientific based information in respect to health risks of drugs of the 2C-series and the detection of their abuse was scarce. Until now no intoxications have been reported in the EU and no centralised legal actions have been taken to prevent possible intoxications. CONCLUSIONS: The lack of observed intoxications may justify the absence of legal actions in the EU against phenethylamine designer drugs-of-abuse of the 2C-series. However, this may also be explained by either the inability of toxicologists to detect the abuse of substances of the 2C-series or the unawareness of the phenomenon of these drugs. Therefore, EU authorities should promote the availability of relevant standards, validated assays and scientific knowledge regarding these drugs.

Designer Drugs↗
PubMed1995

The atom assignment problem in automated de novo drug design. 5. Tests for envelope-directed fragment placement based on molecular similarity.

The fragment placement method has been successfully extended to the problem of envelope-directed design. The atom assignment paradigm was based on molecular similarity between two molecular structures. A composite supersurface is defined to form the surface onto which the molecular fields are projected. The assignment process is then determined by using molecular similarity in the objective function to be optimized. In principle, this procedure is closely similar to that outlined in the previous paper for site-directed design. The rationale has been extensively tested on two benzodiazepine antagonists believed to bind to the same site.

Binding Sites↗
PubMed1995

The atom assignment problem in automated de novo drug design. 2. A method for molecular graph and fragment perception.

If atom assignment onto 3D molecular graphs is to be optimized, an efficient scheme for placement must be developed. The strategy adopted in this paper is to analyze the molecular graphs in terms of cyclical and non-cyclical nodes; the latter are further divided into terminal and non-terminal nodes. Molecular fragments, from a fragments database, are described in a similar way. A canonical numbering scheme for the fragments and the local subgraph of the molecular graph enables fragments to be placed efficiently onto the molecular graph. Further optimization is achieved by placing similar fragments into bins using a hashing scheme based on the canonical numbering. The graph perception algorithm is illustrated in detail.

Algorithms↗
PubMed1993

Molecular surface comparison: application to drug design.

An interactive system for the display and manipulation of molecular surface properties is presented. The property at the molecular surface is mapped onto the sphere by gnomonic projection. This representation allows direct comparison of the surface properties of pairs of molecules. The system allows the user to explore the similarities between a pair of molecules in an interactive manner, and provides extensive visual (color-coded field and field difference maps) and numerical (rms difference value) aids to complement the user's chemical intuition. Examples of the use of the system to study beta-lactam compounds and phosphodiesterase inhibitors are presented.

Anti-Bacterial Agents↗
PubMed1992

Understanding the role of oxyradicals in general and in toxic hepatic damage can help safer drug design.

The existence and importance of free radicals are well established both theoretically and in in vivo experiments. Methods and techniques are now available to demonstrate the formation of free radical metabolites of natural substances and xenobiotics. Theories of the biological effects of free radicals could be unified and used for a better understanding of the complex processes of the organism. Pharmacology can gain profit from this multidisciplinary approach, which helps to design safer drugs. The theories of free radicals and the results of experiments with antioxidants could help to decrease the oxidative stress caused by pharmaceutical chemicals.

Animals↗
PubMed1998

Transcription-factor-modulating agents: precision and selectivity in drug design.

Transcription factors play an important role in the long-term regulation of cell growth, differentiation and responses to environmental cues. There is growing evidence that these proteins are closely associated with control at the genetic level of the development and maintenance of the diseased state, and might therefore provide selective targets for novel pharmaceutical intervention. The vast array of information available on the three-dimensional structure of transcription factors and the intricate molecular machineries that fine-tune their activity offer opportunities for embarking on the rational design of drugs directed against specific transcription factors, thus producing potent new agents that modulate their function in a plethora of clinically important situations.

Computers↗
PubMed2000

Use of an additional hydrophobic binding site, the Z site, in the rational drug design of a new class of stronger trypanothione reductase inhibitor, quaternary alkylammonium phenothiazines.

Improved rationally designed lead drug structures against African trypanosomiasis, Chagas disease, and leishmaniasis were obtained against trypanothione reductase from Trypanosoma cruzi. Substituted-benzyl [3-(2-chloro-4a, 10a-dihydrophenothiazin-10-yl)propyl]dimethylammonium salts, synthesized by Menschutkin quaternization of the tertiary alkylamine omega-nitrogen atom of chlorpromazine, were linear, competitive inhibitors of recombinant trypanothione reductase from T. cruzi, with either trypanothione disulfide or N-benzyloxycarbonyl-L-cysteinylglycyl 3-dimethylaminopropylamide disulfide as substrate. The permanent positive charge on the distal nitrogen atom of the tricyclic side chain contribution to binding was estimated as >/=5.6 kcal.mol(-1) by comparison with the analogue with the cationic nitrogen atom of the quaternary replaced by an ether oxygen atom. A further major contribution to improving K(i) values and inhibition strength was the hydrophobic natures and structures of the N-benzyl substituents. The strongest inhibitor, the [3-(2-chloro-4a,10a-dihydrophenothiazin-10-yl)propyl](3, 4-dichlorobenzyl)dimethylammonium derivative (K(i) 0.12 microM), was approximately 2 orders of magnitude more inhibitory than the parent chlorpromazine. Several of these quaternary phenothiazines completely inhibited T. brucei parasite growth in vitro at <1 microM. Antiparasite activity was not solely determined by inhibition strength against trypanothione reductase, there being a strong contribution from hydrophobicity (for example, benzhydryl-quaternized chlorpromazime had ED(50) < 1 microM). Although active against Leishmania donovani, none of the analogues showed major improvement in this activity relative to chlorpromazine or other nonquaternized phenothiazines. The p-tert-butylbenzyl-quaternized analogue very strongly inhibited (ED(50) < 1 microM) growth of the amastigote stage of T. cruzi.

Animals↗
PubMed1998

Enhancing the flexibility and adaptability of the DARC structural representation for computer-aided drug design.

Noticeable progress has been achieved in the determination of dynamic topochromatic variables for the structural representation of compounds and their situation in a given population. These independent structural variables can be further combined into more complex variables. Their contributions to the evolution of an associated property can therefore be evaluated with certainty. The risk of having correlated variables is avoided while the structural description remains exhaustive. In order to enhance the interpretative ability of the QSAR model, one or several physicochemical properties can be taken with these structural parameters as explanatory variables. Typically, partition coefficients, 3-D and quantum mechanical data are used for this purpose. The structural aspects not taken into account by the physicochemical parameters are reflected in the remaining topochromatic variables. The use of these new concepts is presented in a study of carbazole mutagenicity. The model explains 99% of the total variance with one external property and four additional topochromatic variables. The modulation of the heat of formation of an intermediate by two topochromatic variables suggests a much more precise interpretation than a simple combination of the usual external variables.

Animals↗