ISSN:0272-4391    

DOI:10.1002/ddr.430010402

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1981

数据来源: WILEY

摘要:

AbstractThe study of physicochemical parameters to correlate mathematically chemical structure with biological activity induced by sets of congeneric drugs is now generally referred to as QSAR (quantitative structure‐activity relationships). The ways in which the QSAR paradigm are developing are becoming more varied and complex. Many kinds of parameters are under study in many different groups; various types of mathematical models have been proposed and are being evaluated. Drug researchers are turning more to enzyme modulation to control various biological processes. It is the study of enzyme‐ligand reactions of enzymes whose x‐ray crystallographic structure is known that affords us the means for developing a deeper understanding of QSAR and, at the same time, enhancing our ability to make drugs more selective for various forms of a given enzyme. The union of x‐ray crystallography, moleculargraphics, and QSAR is one of the most exciting new areas of drug development. This report is an introduction to how QSAR is being used to gain insight into the interaction of drugs with macromolecules and macromolecular

ISSN:0272-4391    

DOI:10.1002/ddr.430010403

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1981

数据来源: WILEY

摘要:

AbstractThe significance of enzymes as targets of drug action is discussed. New approaches to the rational design of enzyme inhibitors are characterized by a pronounced shift of emphasis toward the targets of drug action, as the structure and function of an increasing number of enzymes are described in great detail. The most promising of the recently developed approaches is the design of mechanism‐based enzyme inhibitors and, in particular, suicide inactivators. These require enzymic activation of “latent” functional groups to chemically reactive species. The various functionalities currently encountered are reviewed, grouped into chemical categories.The various aspects of the selectivity and the specificity of mechanism‐based enzyme inhibitors, as well as the stability of drug‐enzyme complexes, are discussed in detail. Reversible covalent bond formation is demonstrated by the recovery of thymidylate synthetase activity after inactivation by various 5‐substituted pyrimidine analogs, using purified bacterial enzyme preparations or intact mammalian cells. The fragmentation and secondary reactions of the inhibitor within the complex are described using typical examples of the action of penicillin on its targets and clavulanate on /3‐lactamase, respectively.The perspectives of enzyme inhibitory drug development are discussed, and some of the many areas currently undergoing rapid exploration are mentioned.It is concluded that the rational design of enzyme inhibitors will play an ever‐increasing and significant role in new drug discovery

ISSN:0272-4391    

DOI:10.1002/ddr.430010404

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1981

数据来源: WILEY

摘要:

AbstractRecent progress in opiate receptor research of particular relevance to clinicians is discussed. A simple binding assay, which in itself is valuable in allowing rapid screening of new compounds for opiate activity, has been the basis of these studies. Extensive mapping of opiate receptors in subcortical brain regions has provided important insights into the neuronal pathways involved in analgesia, while physical and chemical characterization of these receptors has led to a simple means of distinguishing agonists from antagonists. The existence of multiple receptors suggests that the analgetic effects of the opiates may be dissociated from other effects, and studies of tolerance and dependence indicate that they too may be dissociable from analgesia. Purification of the receptors, at last a reasonable possibility, may lead to new ways to promote or inhibit analgesia.

ISSN:0272-4391    

DOI:10.1002/ddr.430010405

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1981

数据来源: WILEY

摘要:

AbstractThe identification of useful new drugs, when not due entirely to serendipity, has often relied on in vivo techniques that are both difficult to interpret and to perform. The receptor binding technique, however, by allowing the direct study of the specific biochemical site of action of most psychotherapeutic drugs has provided a simple, selective, and sensitive method to study drug‐receptor interactions. The biochemical locus of action for a family of drugs can often be identified by comparing their absolute potencies in in vivo systems with their affinities at a number of drug and/or neurotrans mitter receptor binding sites. Once a particular binding site is identified as therapeutically relevant, affinity for this binding site can be used as a screen for novel compounds that may show similar in vivo activity. Detailed structure‐activity relationships can be determined in vitro without the problems of metabolism and differential absorption that complicate in vivo studies. Such studies allow the pinpointing of active sites within the drug molecule for further synthetic manipulations. Receptor binding studies have been essential in the elucidation of the therapeutic mechanisms of neuroleptics, tricyclic antidepressants, opiates, and benzodiazepines. Receptor binding studies are not only useful in the identification and quantification of therapeutically useful drug receptor interactions but have also been invaluable in the study of similar interactions that manifest themselves as drug‐induced side effects. Such studies may eventually allow the development of drugs that are not only more therapeutically potent but are also free of side effects. Radioreceptor assays have also been introduced to measureserum drug levels of neuroleptics, antidepressants, anticholinergics, benzodiazepines and P‐adrenergic antagonists. These methods have the advantage of being quick, sensitive, selective, and inex

ISSN:0272-4391    

DOI:10.1002/ddr.430010406

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1981

数据来源: WILEY

摘要:

AbstractThe psychotropic properties of nine compounds were discovered in healthy subjects based on the effects of computer‐analyzed cerebral bioelectrical potentials or computer‐analyzed electroencephalograms (CEEG). Quantitative pharmaco‐EEG (QPEEG) studies demonstrated that CEEG profiles of mianserin (GB‐94), GC‐46, cyclacozine, mesterolone, and estradiol valerate, resembled the CEEG profiles of tricyclic antidepressants. CEEG profiles of d‐ and I‐norgestrel and cyproterone acetate showed similarities to benzodiazepine anxiolytics, and profiles of lisuride hydrogen maleate resembled psychostimulant compounds. Thus, antidepressant, anxiolytic, and “psychostimulant” effects were predicted for these compounds. Subsequent clinical trials confirmed the antidepressant effects of mianserin, GC‐46, and mesterolone in depressed patients; the anxiolytic effects of I‐norgestrel and cyproterone acetate in anxiety syndromes; and the “psychostimulant” properties of lisuride hydrogen maleate in the “geriatric” population. However, animal pharmacology and biochemical investigations failed to predict any psychotropic p

ISSN:0272-4391    

DOI:10.1002/ddr.430010407

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1981

数据来源: WILEY

摘要:

AbstractThree‐dimensional computer graphic systems are an emerging tool in the design of therapeutic compounds. The molecular recognition process involved in drug‐receptor interaction implies a three‐dimensional stereospecificity shared by a set of drugs of similar pharmacological action. In investigating the pharmacophore, it is therefore necessary to go beyond two‐dimensional structures by including the description of the spatial properties of drugs.This review describes both current and potential tools that a graphic computer can support to help the medicinal chemist in his structure‐activity puzzle. An outline of the systems presently in use for this purpose and a summary of recent applications is given. Some current developments undertaken in our research group are presented in the field of opiates, GABA, clonidine, antipsychotics, and S‐adenosyl‐L‐methio

ISSN:0272-4391    

DOI:10.1002/ddr.430010408

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1981

数据来源: WILEY

摘要:

AbstractDNA from a variety of sources may be inserted into the DNA of bacteria (cloned) by means of bacteriophage or plasmid vectors. DNA to be cloned may originate from the genome of another organism (genomic DNA), it may be copied enzymatically from messenger RNA (complementary DNA), or it may be synthesized by purely chemical means. In general, cloning of genomic DNA is useful for studying gene structure, but not useful for inducing bacteria to synthesize the proteins coded by the DNA. This is because the genes of higher organisms usually consist of stretches of DNA coding for parts of a protein which are separated from one another by other DNA (intervening sequences) which does not code for protein. Bacterial genes are not interrupted by intervening sequences, hence bacteria cannot make protein accurately from genes containing such interruptions. The use of complementary DNA or chemically synthesized DNA circumvents this problem. These sources of DNA have been used successfully to produce an increasing number of pharmacologically useful proteins. The bacterial synthesis of insulin, growth hormone, and endorphin are reviewed as examples of the applications of this technology.

ISSN:0272-4391    

DOI:10.1002/ddr.430010409

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1981

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430010401

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1981

数据来源: WILEY