Showing papers in "Current Medicinal Chemistry in 1995"

Biologically active cyclopropanes and cyclopropenes

Abstract: The variety of biological systems which are modulated by naturally occuring cyclopropanes has only been realized recently. They range from antibiotic, antiviral, antifungal and insecticidal activities, control of plant growth and fruit ripening, antimycotic, thyromimetic, hormonal, carcinogenic or antitumoral activities, enzyme and gluconeogenesis inhibitions, to neurochemical activity. Cyclopropanes are also major components of membranes, for instance in tuberculosis cells, and key intermediates in many biosynthetic processes. Many synthetic drugs include cyclopropanes in their structure and they are also widely used to probe the mechanisms of biological processes. Naturally occuring cyclopropenes are known to be potent enzyme inhibitors controlling key processes on the fatty acid desaturation cycle and, in one case, to be an antibacterial agent. Synthetic analogues similarly inhibit pheromone production in insects by blocking pheromone receptors. When they have been demonstrated, the mechanisms responsible for the specific bioactivity of these systems are also reviewed

Macrocyclic peptidomimetics - Forcing peptides into bioactive conformations

Abstract: Cyclic peptides that are potent regulators of biological processes are rapidly emerging as important mechanistic probes and drug leads. Nature clearly uses macrocycles to, constrain peptides into conformations that can selectively bind proteins or small molecules. Therapeutic effects of such macrocycles, often containing additional conformational constraints that fine-tune structure (e.g. D-amino acids, N-methyl substituents, aromatic rings, to name a few), have so far been mainly discovered by accident. However it is now becoming possible to rationally design synthetic macrocycles to selectively recognize and inhibit a specific protein. A receptor-binding structure is more easily adopted by macrocyclic peptidomimetics than more flexible acyclic peptides because the former have less conformational entropy. Macrocycles are often stable to hydrolysis by peptidases that degrade acyclic peptides and hydrophobic side chains can protect peptide bonds in macrocycles from hydrolysis, as well as enhance lipophilicity, cell permeability and bioavailability. Synthetic efforts to obtain bioactive conformations of short peptides have so far been substrate-based, guided by molecular modelling predictions and structure-activity data for modified amino acid sequences of substrates. However, dramatic advances in molecular biology, X-ray crystallography, NMR spectroscopy and computing are rapidly producing three dimensional structures of proteins, promising direct observation of protein-bound conformations of small molecules and receptor-based design of peptidomimetics with surface complementarity for proteins. This perspective review highlights examples of both natural and synthetic bioactive macrocyclic peptides containing constraints that fix conformation, and briefly illustrates the promise that receptor-based design holds for structural and functional mimicry of peptides by macrocycles.

Matrix metalloproteinase inhibitors : current status

Abstract: Due to the increasing evidence for the involvement of the matrix metalloproteinases (MMPs) in a variety of tissue degenerative disorders, such as arthitis and cancer, there is considerable interest in designing agents which inhibit their action, either collectively or selectively. Historically, MMP inhibitors have been designed using knowledge of the substrate cleavage sites of the enzymes, early collagenase inhibitors bearing similarity to the cleavage site of type-I collagen. This review will describe the recent design of specific inhibitors of stromelysin and gelatinase based upon their own substrate preferences. The structure of these inhibitors will be rationalised in terms of the recently published crystal structures of the MMPs. The development of a new generation of peptide-based, yet orally active, inhibitors will be reviewed and their progress towards the clinic assessed. Recent advances in the discovery of non-peptide MMP inhibitors will also be described

β-Lactam compounds. Inhibitors of transpeptidases, β-lactamases and elastases: A review

Abstract: This review takes examples, mostly from β-lactam compounds developed as elastase inhibitors, to illustrate how an understanding of physico-chemical properties and an appreciation of the molecular shape and electronic properties can lead to a better insight into molecular recognition processes. The synthetic methods employed in the synthesis of lead β-lactam compounds as elastase inhibitors are also discussed

Current developments of A2a adenosine receptor antagonists

Abstract: Adenosine regulates a wide range of physiological functions through specific cell membrane receptors. On the basis of pharmacological studies and molecular cloning, four distinct adenosine receptors have been identified and classified as A 1 , A 2a , A 2b and A 3 . These adenosine receptors are members of the G-protein-coupled receptor family. An intense medicinal chemistry effort made over the last 20 years has led to a variety of selective adenosine receptor agonists and antagonists. While all the agonists thus far identified are related to the adenosine structure, the antagonists available belong to different chemical classes. The prototypic antagonists are xanthine derivatives evolved from the natural compounds, caffeine and theophylline. Typically, they are 8-substituted-1,2,3-trialkylxanthine and are A 1 selective antagonists. More recently, 8-styrylxanthines have been found to be selective for A 2a receptors. Other non-xanthine heterocycles are potent A 2a antagonists and possess different degree of selectivity. Selective antagonists are not available yet for A 2b and A 3 receptors. Given the recent developments of A 2a selective antagonists, we have reviewed their chemical structures and biological properties in the attempts to get insight into this emerging class of new interesting compounds. The development of some of the A 2a antagonists will provide better understanding of the role of A 2a receptors in physiological and pathological states. The compounds appear also to have the potential to be useful for the treatment of cerebral ischemia or neurodegenerative disorders, such as Parkinson's disease

Recent advances in the chemistry of potassium channel openers

Abstract: Among the large number of potassium channels so far described, ATP-sensitive K+ channels (K ATP channels) have recently attracted considerable interest since current studies revealed their essential role in diverse fundamental physiological processes. Such ATP-regulated K+ channels have been identified in numerous cell types including endocrine cells, smooth muscle cells, cardiac cells and central neurons. During the last few years, the amount of chemical agents with K+ channel opening properties has greatly expanded. These potassium channel openers (PCOs) are expected to exert their biological activity though activation of K ATP channels. PCOs display several potential clinical applications and are currently used in the treatment of different cardiovascular disorders. However, development of PCOs as new drugs of clinical importance will depend upon their tissue selectivity and their affinity for a single K ATP channel subtype. This review presents recent progresses in the chemistry of PCOs and reports chemical aspects governing their tissue selectivity

Carbohydrates as drugs and potential therapeutics

Abstract: New develpoments in the medicinal chemistry of carbohydrate based drugs is presented. Classification, as well as therapeutic effects and potential applications are discussed. The main objective of this review is to compile literature data on known carbohydrate therapeutics and address a new developments in particularly promising areas of medicinal chemistry utilizing carbohydrates as naw potential drugs

Anthracene-9,10-diones and aza bioisosteres as antitumor agents

Abstract: Naturally occuring quinones which structurally consist of an anthracene-9,10-dione chromophore are important antitumor agents. The anthracycline antibiotics, in particular, doxorubicin, are major chemotherapeutic agents. The pluramycins and the ene-diynes antibiotics also show promise as antitumor agents. Analogues related to mitoxantrone have been synthesized and biologically evaluated and several of these chemotypes show promise for development as anticancer agents. This review will discuss the discovery of cytotoxic anthracene-9,10-diones and the synthesis and antitumor properties of the related aza and diaza bioisoteres

Phosphodiesterasse IV inhibitors: structural diversity and therapeutic potential in asthma

Abstract: The phosphodiesterases (PDEs) represent a group of enzymes controlling levels of intracellular cyclic AMP (cAMp). Because of the ubiquitous effects of this intracellular messenger, inhibitors of these enzymes have widespread effects. Phosphodiesterase IV represents one of the five families of PDE with a presence in smooth muscles and inflammatory cells, selective inhibition of which been predicted to be of therapeutic advantage in asthma. There are 3 main classes of PDE IV inhibitor, relating to analogues of rolipram, nitraquazone, and xanthines. In vitro, PDE IV inhibitors are able to relax smooth muscle from thelung, and to reduce the production of inflammatory mediators from eosinophils, neutrophils, macrophages and lymphocytes. In vivo, these properties lead to bronchodilatation and inhibition of the late reaction and its sequelae that follow antigen challenge in sensitised animals. Clinical results to parallel these indicators of potential benefit in asthmatic patients have not yet been reported, but the panoply of potent and selective PDE IV inhibitors currently being progressed into the clinic will soon test this hypothesis

4-Hydroxypyrones and related templates as nonpeptidic HIV protease inhibitors

Abstract: One promising therapeutic approach for the treatment of HIV infection is inhibition of the viral protease. Although a number of HIV protease inhibitors have been developed, many of the more potent compounds are peptide-derived structures. Since clinical use such compounds is often hindered by poor pharmacokinetics and lengthy syntheses, interest in small, nonpeptidic HIV protease inhibitors has been growing. One of the most encouraging recent developments in the search for these structures is the advent of a new class of competitive inhibitors, the 4-hydroxypyrones. Screening efforts by researchers at The Upjohn Company and Parke-Davis Pharmaceutical Research independently identified the 4-hydroxycoumarins and the 4-hydroxypyrones as lead structures with weak inhibitory activity. Subsequent co-crystallization of these lead compounds with HIV protease showed that the 4-hydroxypyrone ring was functioning as the pharmacophore. These x-ray crystal structures also provided the basis for extensive structure-based drug design work, which led to the discovery of several potent inhibitors in both the 4-hydroxycoumarin and 4-hydroxypyrone classes. In addition, three new classes of derivatives were designed: tetronique acids, the cycloalkylpyranones, and the dihydropyrones. To date, two compounds from The Upjohn Company have entered the clinic for phase I evaluation, a 4-hydroxypyrone and a cyclooctylpyranone. In preclinical evaluation, these candidates, which are both readily accessible synthetically, demonstrated no only promising antiviral activity, but good pharmacokinetic profiles in rats and dogs

Antibody-directed enzyme prodrug therapy (ADEPT) : a targeting strategy in cancer chemotherapy

Abstract: Antibody-directed enzyme prodrug therapy (ADEPT) is a new conceptual approach designed to improve the selectivity of anti-cancer drugs. ADEPT separates the cytotoxic from the targeting function of immunoconjugates in a two phase system that has benefits over one phase chemo-, toxin- or radioimmoconjugates. This review, while discussing the basic principles of ADEPT and the main requirements for all the components (enzymes, prodrugs and antibodies) of the systems, also summarizes the latest results obtained with this technology. The main components of ADEPT are described. These conclude the targeting of cancer cells by the antibody-enzyme conjugates, the enzymatic activation of the prodrugs, the selection of prodrug/drug (and /or enzyme/prodrug) systems. A special emphasis has been placed on the prodrug/drug systems, the rationale behind their design and the in vitro and the in vivo results obtained with the different types of the prodrugs. The analysis of the advantages and disadvantages of the ADEPT system has led to the potential for clinical use of this system, which enables higher drug concentrations at the tumor compared to classical chemotherapy

Structure-activity relationships of synthetic and semisynthetic opioid agonists and antagonists

Abstract: This paper surveys the relationships between the chemical structures and pharmacological activities of natural or semisynthetic 4,5α-epoxymorphinans, synthetic morphinans and benzomorphans. Substitution of the N-methyl group affords strong analgesics, opioid antagonists and mixed agonist-antagonists respectively. The role of opioid agonists and antagonists in the development of opioid receptor models is also discussed

Steroidal and non-steroidal inhibitors of steroid 5α-reductase

Abstract: A good deal of interest exists in developing inhibitors of steroid 5α-reductase (SR) as a therapy for pharmacological disorders associated with elevated levels of dihydrotestosterone (DHT), the product of SR action on testosterone (T). The recent identification of two isoforms of SR (types 1 and 2) has intensified this effort to include the design of isoform selective and dual isoform SR inhibitors. It is anticipated that such inhibitors will provide a more efficient and specific therapy for disorderd including benign prostatic hyperplasia, some prostatic cancers, certian skin disorders and male pattern baldness. The structural features which are responsible for the potency, isoform selectivity and SR species selectivity of the traditional classes of steroid-based inhibitors, typified by epristeride 7 and finasteride 15, have been identified. This information is being applied to the design of new classes of SR inhibitors. A new and rapidly expanding area of this work is the identification of non-steroidal inhibitors of SR. A survey of the main classes of SR inhibitor is followed by a review of the key structural features that are known to influence inhibitor potency and selectivity

Recent developments in the control of Trypanosoma cruzi, the causative agent for Chagas' disease

Abstract: Chagas'disease is a terrible illness that affects million of people in Central and South America. The causative agent for this disease is the hemoflagellate protozoan Trypanosoma (Schizotrypanum) cruzi which is transmitted to the human body by Reduviid insects, such as Triatoma infectans, popularly known as vinvhuca, and Rhodnius prolixus. This parasite is also transmitted by transfusion of infected blood. Despite of the progresses made in chemotherapy, new compounds are needed because the trypanocidal drugs presently in use cause considerable side effects on patients and present lack of efficacy and specificity against all stages of the disease. There is no effective treatment available for Chagas' disease in spite of the important advances made in the study of the biochemistry of the microorganism responsible for the mentioned disease. The urgency for more selective and less toxic drugs has led to evaluate chemical therapy based on the knowledge of T.cruzi biochemistry and the mode ofaction of these compounds. In addition, due to the risk that T.cruzi may be transmitted in blood bank for transfusions, it is very important to have new compounds to kill this parasite in blood to be transfused. At present the drug in use for this purpose suffers from serious limitations concerning its safety. In the present work, the recent advances made in order to control the replication of this parasite are presented

β-Alanyl-L-histidinato zinc: A potent activator in bone formation

Abstract: It is known that zinc is essential for the growth of human and many animals. Bone has one of the highest zinc concentrations of all tissues. Bone growth retardation is a common finding in various conditions associated with zinc deficiency, seggesting a physiological role of zinc in the growth and calcification of bone tissue. Bone zinc content is decreased by development with aging, skeletal unloading and postmenopausal conditions. Thus zinc deficiency may play a pathophysiological role in the deterioration of bone metabolism. In fact, zinc has been demonstrated to have a stimulatory effect on bone formation and mineralization due to promoting bone cellular protein synthesis. AHZ is a new zinc compound, in which zinc is chelated to β-alanyl-L-histidine (L-carnosine). This compound can stimulate bone formation and mineralization in wealing and aged rats, and it has a direct anabolic effect in culture system of bone tissue and bone-forming cells (osteoblastic cells). The stimulatory effect of AHZ on bone formation was more intensive than that of zinc sulfate, showing that the mode of AHZ action differs from that of zinc sulfate. AHZ has s stimulating effect on proliferation and differentiation in osteoblastic cells due to a newly synthesized protein components. It is confirmed that bone-forming effect of AHZ is a greater than that of various bone-regulating hormones and other factors. The oral administration of AHZ has a fine restorative effect on osteopenia with various pathophysiological conditions. AHZ may be new drug in therapy of osteoporosis. Clinical studies are in progress

New analogs of methotrexate in cancer and arthritis

Abstract: Aminopterin and its N 10 -methyl analog, methotrexate, were synthesized in the late 1940s and methotrexate was subsequently incorporated into clinical use as an antitumor agent in the mid-1950s. In more recent years methotrexate has also become accepted as an effective agent for treatment of rheumatoid arthritis. Structure-activity studies have been ongoing over the past 40 years in an effort to develop a safer and more effective version of this pwerful antifolate. Early work featured replacement of nitrogen atoms at various positions in the pterin ring, substituion about the phenyl ring in the side chain and alteration in the glutamic acid subunit. These studies shed considerable light on structural requirements for antitumor activity. However, new agents with serious potential for clinical introduction were not encountered untill structural modification of the region bridging the pterin and benzoyl glutamate side chain took place. A series of 10-substituted-10-deazaaminopterin analogs was investigated and found to have activity superior to methotrexate in several tumor models in vivo. There was in vitro evidence for facilitated transport into tumor cells versus sensitive host tissue cells and increased polyglutamylation within the tumor cells such that a selective accumulation was achieved in tumor tissue. 10-Ethyl-10-deazaaminopterin (edatrexate) was found to be clinically effective against lung and breast solid tumors. Our laboratories have continued to pursue structural modifications of 10-deaza, 5,10-dideaza and 8,10-dideazaaminopterins in an effort to improve upon the efficacy of edatrexate. Additional variation has been made in the bridge region and various heterocyclic rings have been introduced in place of the side chain phenyl ring. These modifications have resulted in additional new antitumor agents and compounds with activity exceeding that of methotrexate in rheumatoid arthritis

Drugs for osteoporosis prevention : mechanisms of bone maitenance

Abstract: Unchecked bone density loss can lead to osteoporosis. Such loss arises from a variety of metabolic imbalances, in particular hormonal insufficiency in postmenopausal women. Bone densitometry, coupled with appropriate monitoring of bone turnover markers osteocalcin and (deoxy)pyridinoline, enables early diagnosis. This review will focus on recent advances concerning the biochemical and histomorphometric bases for clinically effective bone loss prevention by new and established medicinal agents. Estrogen replacement therapy generally has involved steroidal estrogens, given as mixed sulfate ester conjugates composed mainly of estrone and equilin. Current experimental evidence suggests no major difference in the biochemical function of these steroidal estrogens, or their resoective 17β-hydroxy counterparts. Nonsteroidal estrogen receptor ligands such tamoxifen, raloxifene, and droloxifene, like estradiol, act as selective estrogen agonist in bone. But unlike estradiol, they are antagonists in other tissues. This selective estrogenicity might offer advantages over conventional estrogens, such as a decreased incidence of carcinogenicity. However, therapy with tamoxifen, the most widely used of these, has been associated with reproductive tract toxicity. And in laboratory rats, tamoxifen is converted to DNA-reactive hepatocarcinogenic metabolites. Propects for bone loss suppressive drugs with a more diverse range of applications and low toxicity potential are embodied in the bisphosphonate etidronate and its analogues: risedronate, alendronate; ibandronate, pamidronate, and cimandronate. Ipriflavone, an isoflavone derivative, augmented the effect of conjugated estrogens, enabling dose reduction of the latter in postmenopausal osteoporosis. Constricted analogues of parathyroid hormone hold future promise in bone restoration therapy

Strategies for the development of photodynamic sensitizers

Abstract: The use of light activated dyes in photomedicine offers the potential to administer to patients an inert compound which can be selectively activated by photoirradiation. Such a process allows for unique control of the photochemotherapeutic process, using techniques to enhance grug targeting and/or selective irradiation of target tissues. Substantial progress has been made in recent years in developing biologically compatible photosensitizers and in understanding their mechanisms of action. In one field of photomedicine called photodynamic therapy, excitation of the sensitizer leads to the generation of activated oxygen species which then oxidize biological substrates such as protein and lipids. Since different sensitizers localize in different cell types and in different subcellular organelles, the mechanisms of cell necrosis may differ. Current research is aimed at better understanding the parameters responsible for these properties of photosensitizers and in expanding the disease indications to which phototherapy can be applied

Strategies to find novel angiogenesis inhibitors as potential therapeutic agents for cancer

Abstract: The develpoment of therapeutic agents with mechanisms of action different from those of traditional chemotherapeutic drugs is now required in the field of anti-cancer drug therapy, and different approaches to this problem have been made. Considerable attention has been paid to compounds able to interfere with tumor-related angiogenesis. This is due to (1) increasing evidence that both tumor growth and metastasis depend on angiogenesis, and (2) accumulated findings indicating that different types of angiogenesis inhibitors can prevent these two phenomena. Naw it is expected that treatment involving angiogenesis inhibitors will become a new strategy for cancer therapy. This review concerns the approaches we have taken so far for finding novel angiogenesis inhibitors as potential therapeutic agents for cancer

Glyceride conjugates as drug carriers

Abstract: Drug-lipid conjugates have been prepared in order to confer the attached drugs to the metabolic pathways of natural lipids. The drug can be covalently bound either to a fatty acid or to a glycerid. In glycerides, one or two fatty acid moieties have been replaced by a drug realizing pseudoglycerides. These pseudoglycerides exhibited some physicochemical properties and absorption characteristics similar to those of natural triglycerides resulting in a different pharmacokinetic and/or pharmacodynamic profile compared that of the parent drug. Non steroid anti-inflammatory drugs such as aspirin, indomethacin, ibuprofen, naproxenand aclofenac were covalently bound to diglycerides in order to reduce the ulcerogenicity of the compounds. Employing the absorption process of dietary fat, pseudoglycerides have been used for the targeting of the lymphatic route in order to avoid the first-pass metabolism of a drug (L-DOPA) and/ or to target the lymphatic system for the treatment of lymphatic metastasis (chlorambucil, melphalan) or filiariasis (melphalan and GABA). Pseudoglycerides and other glycerid-like structures have been evaluated in order to increase the intestinal absorption of poorly water-soluble drugs such as phenytoin. An improvement of the blood-brain barrier penetration of GABA covalently bound to glycerides has been reported in the 80's. A similar approach was followed for L-dopa, glycine, valproate, and the enkephalinase inhibitor thiophan including amide bio-isosteres of glycerides. Radioiodinated agents contianing fluoride and nitroxyl moieties were coupled to glycreides and fatty acids as potential hepatographic agents in nuclear medicine, 19 F- and 1 H-nuclear magnetic resonance imaging, respectively. A variety of phospholipid-linked cytotoxic nucleosides and nucleoside analogs such as ara-C, AZT and acyclovir have been prepared. Compared to the parent drugs the phospholipid analogs exhibited increased antineoplastic activity in vitro and in vivo. The conjugates were also active against tumors and viruses that were resistant against drug itself

Functional models of the antitumor antibiotic bleomycin

Abstract: The naturally occuring glycopeptide bleomycin exhibits both antitumor and antibiotic properties. It has an established place in the clinical treatment of certain human malignancies including squamous cell carcinoma and testicular tumors. Structurally it comprises four distinct domains: i) an anchoring group containing a bithiazole moiety that binds to double helical DNA; ii) a chiral peptidic spacer that positions the individual portions of the molecule on the receptor; iii) a sugar moiety bearing a carbamoyl group; and iv) an active moiety bearing ligands capable of coordinating a metal ion, such as iron and which is involved in the redox chemistry ultimately responsible for site specific DNA damage. The observation of serious side effects, principally pulmonary toxicity, has limited the clinical applications of bleomycin and provides the motivation to develop less toxic and more selective versions of the drug. Once the mechanism of action of bleomycin via oxygen mediated and site specific DNA cleavage was elucidated the possibility arose of designing functional models. This article will review progress from the earliest metal-complexing models to the most recent conjugates that fully mimic the action of the natural product and, moreover, are capable of being directed to alternative target sequences

Free radical generating and scavenging compounds as a new type of drug

Abstract: Recently, the free radical investigations cover a broad field of research related to chemistry, biology, medecine and biochemistry. One of the reasons for this is that the free radicals play crucial roles in many pathogenic disorders, typically carcinogenesis. So, in this sense it is very important to elucidate the precise mechanism of action of free radicals in vivo from the aspect of tumor necrosis. Indeed, many drugs have been extensively studied in relation to free radicals in recent years. These studies can be divided into two categories one of which emphasizes the advantageous side of free radicals, while the other emphasizes the toxic aspects of free radicals. In this review article, we will discuss four major studies related free radical studies based on the chemical standpoint of view. First we will introduce the recent advances of radical generating drugs such as bleomycin and some ene-diyne natural products in the medicinal field. Second, we will introduce the possible use of free radical generating compounds as a candidate of the new-type of drug. Third, we will show the protective effects and importance of some recent advances in antioxidants research, which show the potentiality of natural antioxidants as the protective or therapeutic medicine for free radical diseases. Finally, we will introduce some recent progress in the gene regulation studies by the antioxidants and show our ideas for the future application for this concept in the medicinal fields

Strategies to enhance the localization of anticancer immunoconjugates

Abstract: Monoclonal antibodies (mAb) that bind to tumor-associated antigens have been used to selectively deliver toxic agents such as drugs, radionuclides, or protein toxins to tumors. A number of mAb conjugates have been effective in killing cells in vitro and in causing tumor regressions in mice; but as yet have not been curative against solid tumors in humans. One of the problems that has been identified for mAb tumor targeting is that systemic clearance tends to be slow, resulting in low tumor-to-blood ratios even many days after administration. Many strategies have been explored to accelerate mAb conjugate clearance without affecting intratumoral uptake. This can be accomplished by extracorporeal adsorption or plasmapheresis to remove the conjugate from the blood, or by complexing the conjugate with an agent that is cleared very quickly from the blood. Such agents include carbohydrates, avidin, and mAbs directed against the immunoconjugate. Each of these strategies have been employed to enhance the tumor-to-blood ratio of immunoconjugates

Diarylazepine derivatives as potent atypical neuroleptic drugs: Recent advances

Abstract: Dibenzoazepine derivatives have represented and still represent today an interesting and exciting field of investigation in medicinal chemistry. A slight modification of the tricyclic structure leads to a profound alteration of the activity profile. Indeed, clothiapine is a neuroleptic drug with strong propensity to induce extrapyramidal side effects (EPS) while clozapine possesses an atypical neuroleptic profile and produces only minimal EPS. The action mechanisms of clozapine have not been completely elucidated. Although clozapine represents a great advance in the treatment of psychiatric disorders, the induction of dramatic toxic effects has stimulated the search for an alternative to clozapine. This challenge is currently the focus of the most active efforts in contemporary neuropharmacology. This review attempts to describe the development of atypical neuroleptic drugs through the diarylazepine series, a promising and modulable class of compounds

Chirality and computational chemistry: A new direction

Abstract: Physical and biological responses to natural and synthetic chemicals occur only at molecular distances and at molecular dimensions. Computational chemistry calculates results in molecular dimensions, but has serious difficulties in accurately predicting chiral interactions between distereoisomers and/ or enantiomers. Prediction of structures and conformations for more complicated chiral interactions such as in protein folding and protein binding may be intrinsically inaccurate because the molecular consequences of the forces between these spatially close chiral centers are not explicitly taken into account. Molecular forces are calculated within and between molecules by optimizing the variables of distance, shape, and time. Symmetry in space over a distance is not the same as symmetry in space over a period of time. Thus for asymmetrical chemical structures, time distorts the mirror of chirality. The physical chemical properties of unequal population of R- and S-isomers of any compound are not directly predictable from those of binary mixtures containing equal amounts of opposite isomers. Only if the corresponding populations of R- and S-isomers are exactly equal can molecular properties be explained by time independent variables. Ignoring time-dependent variables inherently precludes understanding time dependent conformational and configurational changes which occur in xenobiotics, hormones, peptides and other chiral compounds which occur in an asymmetrical chemical environment